Descriptor: "MESH: Neurons" - Searchworks@Jio Institute Digital Library Search Results

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816 results on '"MESH: Neurons"'

1. SNORD116 and growth hormone therapy impact IGFBP7 in Prader–Willi syndrome

Author: Lisa Cole Burnett, Françoise Conte Auriol, Eric Bieth, Jean Pierre Salles, Juliette Salles, Maithé Tauber, Gwenaelle Diene, Catherine Molinas, Rudolph L. Leibel, Boris V. Skryabin, Isabelle Gennero, Timofey S. Rozhdestvensky, Sanaa Eddiry, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence du Syndrome de Prader-Willi, Pôle Enfants [CHU Toulouse], Service Psychiatrie et psychologie médicale [CHU Toulouse], Pôle Psychiatrie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Illinois [Chicago] (UIC), University of Illinois System, Columbia University [New York], and Pistre, Karine
Subjects: 0301 basic medicine, MESH: Prader-Willi Syndrome* / genetics, medicine.medical_specialty, MESH: RNA, Small Nucleolar, congenital, hereditary, and neonatal diseases and abnormalities, IGFBP7, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, MESH: Neurons, MESH: Induced Pluripotent Stem Cells, Article, MESH: Prader-Willi Syndrome* / drug therapy, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, RNA, Small Nucleolar, MESH: Animals, MESH: Mice, Genetics (clinical), Neurons, MESH: Humans, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Dopaminergic, nutritional and metabolic diseases, medicine.disease, Phenotype, Pathophysiology, nervous system diseases, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, MESH: Growth Hormone, Growth Hormone, Knockout mouse, business, Genomic imprinting, Prader-Willi Syndrome, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Purpose: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS.Methods: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness.Results: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1.Conclusion: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.
Published: 2021
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2. Physiological synaptic activity and recognition memory require astroglial glutamine

Author: Giselle Cheung, Danijela Bataveljic, Josien Visser, Naresh Kumar, Julien Moulard, Glenn Dallérac, Daria Mozheiko, Astrid Rollenhagen, Pascal Ezan, Cédric Mongin, Oana Chever, Alexis-Pierre Bemelmans, Joachim Lübke, Isabelle Leray, Nathalie Rouach, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), Photophysique et Photochimie Supramoléculaires et Macromoléculaires (PPSM), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute of Neuroscience and Medicine [Jülich] (INM-1), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry, Psychotherapy and Psychosomatics [Aachen], and Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH)
Subjects: Male, MESH: Hippocampus, Intravital Microscopy, MESH: Mice, Transgenic, Glutamine, Science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Glutamic Acid, MESH: Stereotaxic Techniques, General Physics and Astronomy, Mice, Transgenic, MESH: Cognition, MESH: Rhodamines, Hippocampus, Synaptic Transmission, General Biochemistry, Genetics and Molecular Biology, Stereotaxic Techniques, Mice, MESH: Intravital Microscopy, Cognition, MESH: Recognition, Psychology, MESH: Synaptic Transmission, Animals, MESH: Animals, MESH: Mice, Fluorescent Dyes, Neurons, MESH: Glutamine, Multidisciplinary, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Rhodamines, MESH: Molecular Probes, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Recognition, Psychology, MESH: Glutamic Acid, General Chemistry, MESH: Fluorescent Dyes, MESH: Male, MESH: Astrocytes, MESH: Models, Animal, Astrocytes, Molecular Probes, Models, Animal, ddc:500
Abstract: Nature Communications 13, 753 (2022). doi:10.1038/s41467-022-28331-7, Published by Nature Publishing Group UK, [London]
Published: 2022
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3. Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson’s disease

Author: Victor, Girard, Florence, Jollivet, Oskar, Knittelfelder, Marion, Celle, Jean-Noel, Arsac, Gilles, Chatelain, Daan M, Van den Brink, Thierry, Baron, Andrej, Shevchenko, Ronald P, Kühnlein, Nathalie, Davoust, Bertrand, Mollereau, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Unité Maladies Neuro-Dégénératives (MND), Laboratoire de Lyon [ANSES], Université de Lyon-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université de Lyon-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institute of Molecular Biosciences, Karl-Franzens University Graz, (IMB), and Karl-Franzens-Universität Graz
Subjects: Photoreceptors, Sensory Receptors, Hydrolases, [SDV]Life Sciences [q-bio], MESH: Neurons, Social Sciences, QH426-470, Biochemistry, Animals, Genetically Modified, Neuroblastoma, Animal Cells, Medicine and Health Sciences, Drosophila Proteins, Psychology, Lipases, Parkinson, MESH: Lipid Metabolism, Neurons, Drosophila Melanogaster, Hydrolysis, Chemical Reactions, Eukaryota, Parkinson Disease, Animal Models, Proteases, Lipids, Enzymes, Insects, Chemistry, Experimental Organism Systems, Physical Sciences, alpha-Synuclein, Sensory Perception, Drosophila, Cellular Types, Anatomy, Research Article, Signal Transduction, Arthropoda, MESH: Drosophila Proteins, Lipolysis, Ocular Anatomy, Research and Analysis Methods, Protein Aggregation, Pathological, MESH: Lipid Droplets, Perilipin-2, Retina, MESH: Animals, Genetically Modified, Model Organisms, Ocular System, MESH: alpha-Synuclein, Genetics, Animals, Humans, Cognitive Psychology, Organisms, Membrane Transport Proteins, Biology and Life Sciences, Afferent Neurons, Proteins, Lipid Droplets, Cell Biology, Lipid Metabolism, Invertebrates, Disease Models, Animal, Cellular Neuroscience, Proteolysis, Animal Studies, Enzymology, Cognitive Science, Perception, Zoology, Entomology, MESH: Parkinson Disease, Neuroscience
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/midway, fatty acid transport protein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons., Author summary Parkinson’s disease (PD) is a neurodegenerative disease characterized by the neurotoxic aggregation of the alpha-synuclein (αSyn) protein. Cellular models of the disease are also associated with an abnormal fat storage in the form of lipid droplets (LDs). However, in which cells, neuron or glial cells, LDs accumulate in the organism remains unknown. To understand the relationship between αSyn and the accumulation of LDs, we used a Drosophila (fruit fly) model of PD. We found that, in the presence of a protein that coats LDs, perilipin, LDs accumulate in photoreceptor neurons of the fly. Interestingly, the accumulation of LDs induced by perilipin or other LD-coating proteins was enhanced in the presence of αSyn. Using human neuronal cell lines and the fly, we could show that LD-coating and αSyn proteins localize at the surface of LDs. Finally, we observed that the process of αSyn aggregation was enhanced in the presence of LDs by using a biochemical approach. We thus propose that the association of αSyn with LDs could contribute to αSyn aggregation and progression of the pathology.
Published: 2021
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4. Extracellular and intracellular components of the impedance of neural tissue

Author: Claude Bedard, Charlotte Piette, Laurent Venance, Alain Destexhe, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and PERIGNON, Alain
Subjects: Neurons, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biophysics, MESH: Neurons, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Electric Conductivity, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Brain, MESH: Electric Conductivity, MESH: Electrodes, MESH: Brain, Electric Impedance, MESH: Electric Impedance, Electrodes, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Abstract: International audience; Electric phenomena in brain tissue can be measured using extracellular potentials, such as the local field potential, or the electro-encephalogram. The interpretation of these signals depends on the electric structure and properties of extracellular media, but the measurements of these electric properties are still debated. Some measurements point to a model in which the extracellular medium is purely resistive, and thus parameters such as electric conductivity and permittivity should be independent of frequency. Other measurements point to a pronounced frequency dependence of these parameters, with scaling laws that are consistent with capacitive or diffusive effects. However, these experiments correspond to different preparations, and it is unclear how to correctly compare them. Here, we provide for the first time, impedance measurements (in the 1-10 kHz frequency range) using the same setup in various preparations, from primary cell cultures to acute brain slices, and a comparison with similar measurements performed in artificial cerebrospinal fluid with no biological material. The measurements show that when the current flows across a cell membrane, the frequency dependence of the macroscopic impedance between intracellular and extracellular electrodes is significant, and cannot be captured by a model with resistive media. Fitting a mean-field model to the data shows that this frequency dependence could be explained by the ionic diffusion mainly associated with Debye layers surrounding the membranes. We conclude that neuronal membranes and their ionic environment induce strong deviations to resistivity that should be taken into account to correctly interpret extracellular potentials generated by neurons.
Published: 2021
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5. KIF13A drives AMPA receptor synaptic delivery for long-term potentiation via endosomal remodeling

Author: Cédric Delevoye, Sergio López-García, José A. Esteban, Yolanda Gutiérrez, Silvia Gutiérrez-Eisman, Argentina Lario, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ministerio de Ciencia e Innovación (España), Institut National de la Santé et de la Recherche Médicale (France), Institut Curie, Centre National de la Recherche Scientifique (France), and Ministerio de Educación y Ciencia (España)
Subjects: Male, MESH: Hippocampus, MESH: Rats, Long-Term Potentiation, MESH: Neurons, Kinesins, Endosomes, AMPA receptor, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Hippocampus, Article, MESH: Synapses, Motor protein, 03 medical and health sciences, 0302 clinical medicine, MESH: Long-Term Potentiation, LTP induction, Animals, MESH: Animals, Receptors, AMPA, Rats, Wistar, Cytoskeleton, 030304 developmental biology, Neurons, 0303 health sciences, Trafficking, musculoskeletal, neural, and ocular physiology, Glutamate receptor, Long-term potentiation, Cell Biology, MESH: Rats, Wistar, MESH: Male, Rats, Cell biology, nervous system, MESH: Endosomes, MESH: Receptors, AMPA, Synapses, Endosomal transport, Synaptic plasticity, Kinesin, Female, MESH: Kinesin, MESH: Female, 030217 neurology & neurosurgery, Neuroscience
Abstract: Gutiérrez et al. describe a novel function for the molecular motor KIF13A, in complex with centaurin-α1, for the insertion of AMPA receptors at synapses during long-term potentiation. This process is mediated by the remodeling of intracellular endosomal compartments in the dendritic shaft., The regulated trafficking of AMPA-type glutamate receptors (AMPARs) from dendritic compartments to the synaptic membrane in response to neuronal activity is a core mechanism for long-term potentiation (LTP). However, the contribution of the microtubule cytoskeleton to this synaptic transport is still unknown. In this work, using electrophysiological, biochemical, and imaging techniques, we have found that one member of the kinesin-3 family of motor proteins, KIF13A, is specifically required for the delivery of AMPARs to the spine surface during LTP induction. Accordingly, KIF13A depletion from hippocampal slices abolishes LTP expression. We also identify the vesicular protein centaurin-α1 as part of a motor transport machinery that is engaged with KIF13A and AMPARs upon LTP induction. Finally, we determine that KIF13A is responsible for the remodeling of Rab11-FIP2 endosomal structures in the dendritic shaft during LTP. Overall, these results identify specific kinesin molecular motors and endosomal transport machinery that catalyzes the dendrite-to-synapse translocation of AMPA receptors during synaptic plasticity.
Published: 2021
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6. Mapping the molecular and cellular complexity of cortical malformations

Author: Fiona Francis, Silvia Cappello, Esther Klingler, Denis Jabaudon, University of Geneva [Switzerland], Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Geneva University Hospital (HUG), Max Planck Institute of Psychiatry, and Max-Planck-Gesellschaft
Subjects: Neurogenesis, MESH: Neurons, Disease, MESH: Nervous System Diseases, 03 medical and health sciences, Mice, 0302 clinical medicine, MESH: Behavior, Cell Movement, MESH: Gene Expression Regulation, Developmental, Neural Pathways, medicine, MESH: Mental Disorders, Animals, Humans, MESH: Animals, Clinical phenotype, Gene, MESH: Cell Movement, MESH: Mice, MESH: Organ Specificity, 030304 developmental biology, Regulation of gene expression, Cerebral Cortex, Neurons, 0303 health sciences, Behavior, Multidisciplinary, MESH: Humans, MESH: Neural Pathways, Mental Disorders, Cortical malformations, Gene Expression Regulation, Developmental, Cognition, MESH: Cerebral Cortex, MESH: Neurogenesis, medicine.anatomical_structure, Cerebral cortex, Organ Specificity, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nervous System Diseases, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.
Published: 2021
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7. Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia

Author: Sarah E.M. Stephenson, Stéphanie Baulac, A. Simon Harvey, Paul J. Lockhart, Homa Adle-Biassette, Mathilde Chipaux, Sara Baldassari, Richard J. Leventer, Wirginia J. Maixner, Wei Shern Lee, Murdoch Children's Research Institute (MCRI), University of Melbourne, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d′Anatomie et de Cytologie Pathologiques [Lariboisiere], Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, Pathology, Somatic cell, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, medicine.disease_cause, Hemimegalencephaly, 0302 clinical medicine, MESH: Child, MESH: Malformations of Cortical Development, Medicine, Child, Laser capture microdissection, Neurons, Mutation, biology, General Neuroscience, TOR Serine-Threonine Kinases, Brain, Malformations of Cortical Development, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, MESH: Hemimegalencephaly, Female, Brief Communications, RC321-571, RHEB, medicine.medical_specialty, MESH: Mutation, Neurosciences. Biological psychiatry. Neuropsychiatry, Brief Communication, 03 medical and health sciences, Young Adult, MESH: Brain, Downregulation and upregulation, Humans, RC346-429, PI3K/AKT/mTOR pathway, MESH: TOR Serine-Threonine Kinases, Epilepsy, MESH: Humans, business.industry, MESH: Child, Preschool, Cortical dysplasia, medicine.disease, MESH: Ras Homolog Enriched in Brain Protein, MESH: Male, 030104 developmental biology, biology.protein, Ras Homolog Enriched in Brain Protein, Neurology. Diseases of the nervous system, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain directly correlated with the somatic variant load.
Published: 2021
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8. Sensory Discrimination of Blood and Floral Nectar by Aedes aegypti Mosquitoes

Author: Carolyn S. McBride, Thomas L. Carroll, Zhongyan Gong, Manu Prakash, Felix J. H. Hol, Trevor R. Sorrells, Veronica Jove, Zhilei Zhao, Leslie B. Vosshall, Rockefeller University [New York], Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Stanford University, Princeton University, Kavli Neural Systems Institute, Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was supported in part by NCATS NIH CTSA grant UL1 TR000043, NIH T32-MH095246 (to V.J.), an HHMI Gilliam fellowship (to V.J.), NSF DGE-1325261 (to V.J.), the CASI/Burroughs Wellcome Fund (to F.J.J.H.), Marie Skłodowska-Curie grant agreement 841893 – PiQiMosqBite (to F.J.J.H.), a Jane Coffin Childs postdoctoral fellowship (to T.R.S.), a Kavli Neural Systems Institute postdoctoral fellowship (to T.R.S.), NIDCD R00-DC012069 (to C.S.M.), NIH DP2-AI124336 (to M.P.), and a USAID Grand Challenges: Zika and Future Threats award (to M.P.). M.P. is an HHMI-Gates Faculty Scholar of the Howard Hughes Medical Institute. C.S.M. is a New York Stem Cell Foundation – Robertson Investigator. L.B.V. is an investigator of the Howard Hughes Medical Institute., and European Project: 841893,H2020-MSCA-IF-2018,PiQiMosqBite(2019)
Subjects: 0301 basic medicine, Taste, nectar-feeding behavior, MESH: Neurons, gustatory receptors, GCaMP calcium imaging, ionotropic receptors, MESH: Discrimination, Psychological, 0302 clinical medicine, Aedes aegypti, Discrimination, Psychological, Aedes, MESH: Animals, Neurons, MESH: Plant Nectar, General Neuroscience, food and beverages, Taste Perception, MESH: Aedes, 3. Good health, Stylet, medicine.anatomical_structure, Blood, MESH: Feeding Behavior, stylet, Plant Nectar, education, Zoology, Sensory system, mosquito, Biology, Article, 03 medical and health sciences, parasitic diseases, medicine, MESH: Blood, Nectar, Animals, [SCCO.NEUR]Cognitive science/Neuroscience, fungi, Feeding Behavior, Blood meal, biology.organism_classification, Sexual dimorphism, 030104 developmental biology, MESH: Taste Perception, blood-feeding behavior, chemogenetics, MESH: Taste, Neuron, 030217 neurology & neurosurgery
Abstract: Blood-feeding mosquitoes survive by feeding on nectar for metabolic energy but require a blood meal to develop eggs. Aedes aegypti females must accurately discriminate blood and nectar because each meal promotes mutually exclusive feeding programs with distinct sensory appendages, meal sizes, digestive tract targets, and metabolic fates. We investigated the syringe-like blood-feeding appendage, the stylet, and discovered that sexually dimorphic stylet neurons taste blood. Using pan-neuronal calcium imaging, we found that blood is detected by four functionally distinct stylet neuron classes, each tuned to specific blood components associated with diverse taste qualities. Stylet neurons are insensitive to nectar-specific sugars and respond to glucose only in the presence of additional blood components. The distinction between blood and nectar is therefore encoded in specialized neurons at the very first level of sensory detection in mosquitoes. This innate ability to recognize blood is the basis of vector-borne disease transmission to millions of people worldwide.
Published: 2020
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9. Rab35 and its effectors promote formation of tunneling nanotubes in neuronal cells

Author: Nina Ljubojevic, Arnaud Echard, Chiara Zurzolo, Shaarvari Bhat, Seng Zhu, Mitsunori Fukuda, Trafic membranaire et Pathogénèse - Membrane Traffic and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Tohoku University [Sendai], Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, We are also grateful for the financial support of Institut Pasteur (Paris). S.B. is supported by JPND-NeuTARGETs-ANR-14-JPCD-0002-02 and INSERM (HTE201602). N.L. is supported by Sorbonne Université—doctoral grant number 3210/2018. S.Z. was supported by Ph.D. fellowships from the China Scholarship Council (201306170046) and by an Institute Carnot fellowship., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: ADP-Ribosylation Factors, MESH: Vesicular Transport Proteins, Vesicular Transport Proteins, MESH: Neurons, lcsh:Medicine, MESH: Microscopy, Fluorescence, MESH: Flow Cytometry, GTPase, Small GTPases, Membrane trafficking, MESH: GTPase-Activating Proteins, Mice, 0302 clinical medicine, MESH: Cytoplasmic Vesicles, MESH: Animals, lcsh:Science, Neurons, 0303 health sciences, Multidisciplinary, Nanotubes, Effector, Chemistry, ADP-Ribosylation Factors, Vesicle, GTPase-Activating Proteins, Flow Cytometry, Cell biology, MESH: Nanotubes, Neurite, MESH: Microscopy, Electron, Scanning, Blotting, Western, Endosomes, Article, Cell Line, 03 medical and health sciences, Organelle, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH: Blotting, Western, MESH: Mice, 030304 developmental biology, lcsh:R, Cytoplasmic Vesicles, Actin cytoskeleton, MESH: Cell Line, MESH: rab GTP-Binding Proteins, Microscopy, Fluorescence, Cell culture, ADP-Ribosylation Factor 6, rab GTP-Binding Proteins, Microscopy, Electron, Scanning, lcsh:Q, Rab, 030217 neurology & neurosurgery
Abstract: Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules. Rab GTPases are the major regulators of vesicle trafficking and also participate in actin cytoskeleton remodelling, therefore, we examined their role in TNTs. Rab35 functions with several proteins that are involved in vesicle trafficking such as ACAP2, MICAL-L1, ARF6 and EHD1, which are known to be involved in neurite outgrowth. Here we show that Rab35 promotes TNT formation and TNT-mediated vesicle transfer in a neuronal cell line. Furthermore, our data indicates that Rab35-GTP, ACAP2, ARF6-GDP and EHD1 act in a cascade mechanism to promote TNT formation. Interestingly, MICAL-L1 overexpression, shown to be necessary for the action of Rab35 on neurite outgrowth, showed no effect on TNTs, indicating that TNT formation and neurite outgrowth may be processed through similar but not identical pathways, further supporting the unique identity of these cellular protrusions.
Published: 2020
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10. Tissue-wide coordination of epithelium-to-neural stem cell transition in the Drosophila optic lobe requires Neuralized

Author: Chloé Shard, François Schweisguth, Juan Luna-Escalante, Génétique du Développement de la Drosophile, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physique de l'ENS - ENS Paris (LPENS (UMR_8023)), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was funded by the Agence Nationale de la Recherche (ANR-10-LABX-0073) and Fondation pour la Recherche Médicale (FRM-DEQ20180339219)., We thank Y. Bellaïche, A. Brand, Y. Cai, L. Cheng, D. Glover, Y. Hong, Y. N. Jan, M. Krahn, F. Matsuzaki, A. Salzberg, M. Sato, J. Skeath, M. Suzanne, A. Wodarz, the Developmental Studies Hybridoma Bank, Flybase, and Image Analysis Hub of the Institut Pasteur for reagents and resources. We thank S. Herbert (Image Analysis Hub), R. Levayer, J.-Y. Tinevez (Image Analysis Hub), T. Schweisguth, and L. Valon for help in segmentation, local z-projection, and image data analysis, M. Rujano for help in live imaging, and L. Couturier for technical help. We thank S. Chanet, E. Contreras, A. Hakes, and G. Perez-Mockus for critical reading., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Laboratoire de physique de l'ENS - ENS Paris (LPENS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Département de Physique de l'ENS-PSL, École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)
Subjects: MESH: Neural Stem Cells, MESH: Drosophila Proteins, MESH: Optic Lobe, Nonmammalian, MESH: Neurons, Biology, MESH: Drosophila melanogaster, 03 medical and health sciences, 0302 clinical medicine, Myosin, medicine, MESH: Animals, Epithelial–mesenchymal transition, Progenitor cell, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, 0303 health sciences, Apical constriction, Cell Biology, MESH: Ubiquitin-Protein Ligases, Neural stem cell, Epithelium, MESH: Morphogenesis, Cell biology, Neuroepithelial cell, MESH: Epithelium, medicine.anatomical_structure, Stem cell, MESH: Cell Polarity, 030217 neurology & neurosurgery
Abstract: International audience; Many tissues are produced by specialized progenitor cells emanating from epithelia via epithelial-to-mesenchymal transition (EMT). Most studies have so far focused on EMT involving single or isolated groups of cells. Here we describe an EMT-like process that requires tissue-level coordination. This EMT-like process occurs along a continuous front in the Drosophila optic lobe neuroepithelium to produce neural stem cells (NSCs). We find that emerging NSCs remain epithelial and apically constrict before dividing asymmetrically to produce neurons. Apical constriction is associated with contractile myosin pulses and involves RhoGEF3 and down-regulation of the Crumbs complex by the E3 ubiquitin ligase Neuralized. Anisotropy in Crumbs complex levels also results in accumulation of junctional myosin. Disrupting the regulation of Crumbs by Neuralized lowered junctional myosin and led to imprecision in the integration of emerging NSCs into the front. Thus, Neuralized promotes smooth progression of the differentiation front by coupling epithelium remodeling at the tissue level with NSC fate acquisition.
Published: 2020
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11. Young Neurons Tickle Memory during REM Sleep

Author: Claire Rampon, Christelle Peyron, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Centre de Recherches sur la Cognition Animale (CRCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Peyron, Christelle, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI)
Subjects: 0301 basic medicine, MESH: Hippocampus, MESH: Sleep, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], education, MESH: Neurons, Sleep, REM, Hippocampus, Hippocampal formation, 03 medical and health sciences, 0302 clinical medicine, Hardware_GENERAL, Memory formation, medicine, MESH: Memory Consolidation, Sleep period, Episodic memory, Memory Consolidation, Neurons, General Neuroscience, Sleep in non-human animals, MESH: Sleep, REM, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Memory consolidation, Neuron, Sleep, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Memory formation is a dynamic process and sleep is part of it. Consolidation of memories relies on finely orchestrated brain activities occurring during the post-learning sleep period. In this issue of Neuron, Kumar and colleagues provide evidence that the activity of adult-born hippocampal neurons, during REM sleep, is critical for the consolidation of episodic memory.
Published: 2020
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12. Eyes Wide Open on AMPAR Trafficking during Motor Learning

Author: Daniel Choquet, Frédéric Gambino, Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiologie cellulaire de la synapse (PCS), and Université Bordeaux Segalen - Bordeaux 2-Institut François Magendie-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, MESH: Protein Transport, genetic structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, education, MESH: Neurons, AMPA receptor, Biology, MESH: Dendrites, Article, 03 medical and health sciences, 0302 clinical medicine, Neuroplasticity, medicine, Receptors, AMPA, MESH: Neuronal Plasticity, Neurons, Neuronal Plasticity, General Neuroscience, musculoskeletal, neural, and ocular physiology, Dendrites, Protein Transport, Motor task, 030104 developmental biology, Visual cortex, medicine.anatomical_structure, nervous system, MESH: Receptors, AMPA, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuron, Motor learning, Neuroscience, 030217 neurology & neurosurgery
Abstract: Modulation of synaptic strength through trafficking of AMPA receptors (AMPARs) is a fundamental mechanism underlying synaptic plasticity, learning, and memory. However, dynamics of AMPAR trafficking in vivo and its correlation with learning have not been resolved. Here, we used in vivo two-photon microscopy to visualize surface AMPARs in mouse cortex during the acquisition of a forelimb reaching task. Daily training leads to an increase in AMPAR levels at a subset of spatially clustered dendritic spines in the motor cortex. Surprisingly, we also observed increases in spine AMPAR levels in the visual cortex. There, synaptic potentiation depends on the availability of visual input during motor training and optogenetic inhibition of visual cortex activity impairs task performance. These results indicate that motor learning induces widespread cortical synaptic potentiation by increasing the net trafficking of AMPARs into spines, including in non-motor brain regions.
Published: 2020
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13. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author: Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Subjects: Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract: International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Published: 2020
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14. Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses

Author: Ana Paula Menegolla, Terrence J. Sejnowski, Tomas M. Bartol, Julia Goncalves, Come Camus, Michel Vivaudou, Florian Levet, Daniel Choquet, Eric Hosy, Jean-Baptiste Sibarita, Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Howard Hughes Medical Institute and the Salk Institute, Howard Hughes Medical Institute (HHMI), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-15-CE11-0029,NEWOPTOGENETICSTOOLS,Nouveaux canaux et transporteurs régulés par la lumière pour l'optogénétique(2015), and Interdisciplinary Institute for Neuroscience (IINS)
Subjects: Patch-Clamp Techniques, MESH: Hippocampus, Intravital Microscopy, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Rats, Sprague-Dawley, Hippocampus, Rats, Sprague-Dawley, Synapse, MESH: Single Molecule Imaging, 0302 clinical medicine, MESH: Animals, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, MESH: Receptor, Metabotropic Glutamate 5, Neurons, 0303 health sciences, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Metabotropic glutamate receptor 5, Chemistry, musculoskeletal, neural, and ocular physiology, Glutamate receptor, MESH: Glutamic Acid, Biological Sciences, Single Molecule Imaging, glutamate receptors, MESH: Receptors, AMPA, Excitatory postsynaptic potential, NMDA receptor, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cells, Cultured, MESH: Rats, Receptor, Metabotropic Glutamate 5, Models, Neurological, Primary Cell Culture, Glutamic Acid, AMPA receptor, Neurotransmission, Receptors, N-Methyl-D-Aspartate, MESH: Primary Cell Culture, 03 medical and health sciences, superresolution microscopy, MESH: Intravital Microscopy, MESH: Models, Neurological, mental disorders, MESH: Patch-Clamp Techniques, MESH: Synaptic Transmission, Animals, synaptic transmission, Receptors, AMPA, 030304 developmental biology, MESH: Receptors, N-Methyl-D-Aspartate, MESH: Embryo, Mammalian, Embryo, Mammalian, Rats, nervous system, Metabotropic glutamate receptor, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule superresolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs. mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.
Published: 2020
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15. Opto nongenetics inhibition of neuronal firing

Author: Nicola Kuczewski, Gwenaelle Laverne, Karima Ait Ouares, Marco Canepari, Corinne Beurrier, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Poulain, Sébastien, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Opsin, Cerebellum, Light, hippocampus, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, striatum, MESH: Neurons, Action Potentials, Hippocampus, Striatum, Hippocampal formation, light stimulation, MESH: Optogenetics, 0302 clinical medicine, MESH: Animals, ComputingMilieux_MISCELLANEOUS, MESH: Action Potentials, Neurons, 0303 health sciences, Chemistry, General Neuroscience, Brain, MESH: Neural Inhibition, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, olfactory bulb, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Olfactory Bulb, mice, cerebellum, MESH: CA1 Region, Hippocampal, Optogenetics, Medium spiny neuron, MESH: Brain, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Animals, optogenetics, CA1 Region, Hippocampal, 030304 developmental biology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neural Inhibition, brain slices, MESH: Cerebellum, MESH: Light, MESH: Male, Olfactory bulb, Mice, Inbred C57BL, Neostriatum, MESH: Neostriatum, nervous system, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Optogenetics is based on the selective expression of exogenous opsins by neurons allowing experimental control of their electrical activity using visible light. The interpretation of the results of optogenetic experiments is based on the assumption that light stimulation selectively acts on those neurons expressing the exogenous opsins without perturbing the activity of naive ones. Here, we report that light stimulation, of wavelengths and power in the range of those normally used in optogenetic experiments, consistently reduces the firing activity of naive Mitral Cells (MCs) and Tufted Neurons in the olfactory bulb as well as in Medium Spiny Neurons (MSNs) in the striatum. No such effect was observed for cerebellar Purkinje and hippocampal CA1 neurons. The effects on MC firing appear to be mainly due to a light-induced increase in tissue temperature, between 0.1 and 0.4°C, associated with the generation of a hyperpolarizing current and a modification of action potential (AP) shape. Therefore, light in the visible range can affect neuronal physiology in a cell-specific manner. Beside the implications for optogenetic studies, our results pave the way to investigating the use of visible light for therapeutic purposes in pathologies associated with neuronal hyperexcitability.
Published: 2018
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16. Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells

Author: Emma Partiot, Nilda Vanesa Ayala-Nunez, Jacky G. Goetz, Gautier Follain, Judith R.E. Roels, Anita Eckly, Béatrice Uring-Lambert, Maxime Chazal, Raphael Gaudin, Gillian Hale, Frank M. J. Jacobs, Sandrine Bourdoulous, Orestis Faklaris, Sherif R. Zaki, Aurélie Hirschler, Nolwenn Jouvenet, Margot Carocci, Florian Bakoa, Sarah Cianférani, Christine Carapito, Frédéric Doussau, Brigid C. Bollweg, François Delalande, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Swammerdam Institute for Life Sciences, University of Amsterdam [Amsterdam] (UvA)-Center for Neurosciences, Génomique virale et vaccination, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), This work has received funding from the French State via the French National Research Agency (ANR) as part of the program Investissements d’avenir (IdEx Université de Strasbourg) to RG. This work was supported by an ATIP-AVENIR starting grant to RG. The research leading to these results has received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7/2007–2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE program coordinated by Campus France, and from the French Agency for Research on AIDS and Viral Hepatitis (ANRS), both attributed to NVAN. Experiments conducted by G.F. and J.G.G. were funded by Plan Cancer (OptoMetaTrap), Ligue contre le Cancer, Idex Attractivités (University of Strasbourg), and by institutional funds from INSERM and University of Strasbourg. G.F. was supported by a doctoral fellowship from Ligue Contre le Cancer. Mass spectrometry experiments were supported by the French Proteomic Infrastructure (ProFI, ANR-10-INBS-08-03). F.B. is a recipient of a PhD grant provided by ANRT (Association Nationale de la Recherche et de la Technologie). N.J. is funded by Agence Nationale pour la Recherche (ANR-16-CE15-0025-01), Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur. CDC contributions to this paper written and edited by G.L.H. and B.C.B. in their private capacity. No official support or endorsement by the Centers for Disease Control and Prevention, Department of Health and Human Services is intended, nor should be inferred. All authors read, provided feedback, and approved the paper. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 NL4-3 AD8 Infectious Molecular Clone (pNL(AD8)) from Dr. Eric O. Freed (cat# 11346)., ANR-16-CE15-0025,Viro-Storm,Mécanismes de production incontrôlée de cytokines au cours de l'infection virale(2016), European Project: 609102,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,PRESTIGE(2014), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), EFS-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), jouvenet, nolwenn, Mécanismes de production incontrôlée de cytokines au cours de l'infection virale - - Viro-Storm2016 - ANR-16-CE15-0025 - AAPG2016 - VALID, PRES Towards International Gain of Excellence - PRESTIGE - - EC:FP7:PEOPLE2014-09-01 - 2019-08-31 - 609102 - VALID, Equipe Direction scientifique, Sciences et Technologies de la Musique et du Son (STMS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Neuro-Immunologie Virale, Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de Photonique Quantique et Moléculaire (LPQM), Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-École normale supérieure - Cachan (ENS Cachan), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion (http://www.u949.inserm.fr/), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique, Département des Sciences Analytiques, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France (LSMBO-DSA-IPHC), Centre National de la Recherche Scientifique (CNRS), Immunorhumathologie moléculaire, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Molecular Neuroscience (SILS, FNWI)
Subjects: Central Nervous System, 0301 basic medicine, MESH: Neurons, General Physics and Astronomy, MESH: Organoids, MESH: Monocytes, Monocytes, Zika virus, 0302 clinical medicine, MESH: Transendothelial and Transepithelial Migration, Cerebellum, MESH: Animals, lcsh:Science, MESH: Embryonic Stem Cells, ComputingMilieux_MISCELLANEOUS, Zebrafish, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Neurons, Multidisciplinary, Zika Virus Infection, Cell adhesion molecule, food and beverages, Sciences du Vivant [q-bio]/Microbiologie et Parasitologie, Phenotype, 3. Good health, Cell biology, Organoids, Mechanisms of disease, medicine.anatomical_structure, MESH: Cell Survival, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Endothelium, Cell Survival, Science, MESH: Zika Virus, Biology, MESH: Endothelium, Article, General Biochemistry, Genetics and Molecular Biology, Virus, MESH: Cell Adhesion, 03 medical and health sciences, Virology, medicine, Animals, Humans, MESH: Central Nervous System, Cellular microbiology, Cell adhesion, MESH: Zebrafish, Embryonic Stem Cells, MESH: Humans, Monocyte, fungi, Transendothelial and Transepithelial Migration, Zika Virus, General Chemistry, biology.organism_classification, Embryonic stem cell, MESH: Cerebellum, Disease Models, Animal, 030104 developmental biology, lcsh:Q, MESH: Disease Models, Animal, Cell Adhesion Molecules, MESH: Female, 030217 neurology & neurosurgery
Abstract: Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention., Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.
Published: 2019
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17. Memo1-Mediated Tiling of Radial Glial Cells Facilitates Cerebral Cortical Development

Author: Victoria Arevalo, Tamille Rhynes, Keiko Yabuno-Nakagawa, Oleh Krupa, Suriya Thompson, Naoki Nakagawa, Jingjun Li, Chu-Wei Huang, Zoltán Molnár, Jason L. Stein, Janice Lee, Amelia Lee, Aditi Adhikari, Charlotte Plestant, Ali Badache, Eva S. Anton, Department of Cell Biology and Physiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Department of Physiology, Anatomy and Genetics, University of Oxford [Oxford], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Departments of Medicine and Cell Biology & Physiology, University of California (UC)-University of California (UC), University of Oxford, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, MESH: Neural Stem Cells, MESH: Hippocampus, genetic structures, [SDV]Life Sciences [q-bio], radial glia, MESH: Neurons, Neocortex, MESH: Receptors, G-Protein-Coupled, Hippocampus, Microtubules, Receptors, G-Protein-Coupled, Mice, MESH: Neocortex, 0302 clinical medicine, Neural Stem Cells, MADM, Cell Movement, Cerebellum, MESH: Animals, MESH: Cell Movement, Cerebral Cortex, Neurons, Gene knockdown, Chemistry, MESH: Microtubules, General Neuroscience, Intracellular Signaling Peptides and Proteins, Cell Polarity, MESH: Ependymoglial Cells, Cell biology, Protein Transport, medicine.anatomical_structure, Cerebral cortex, Gene Knockdown Techniques, MESH: HEK293 Cells, MESH: Cell Polarity, Microtubule-Associated Proteins, MESH: Protein Transport, animal structures, Ependymoglial Cells, MESH: Autistic Disorder, Motility, autism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Mediator, Microtubule, MESH: Intracellular Signaling Peptides and Proteins, medicine, microtubule minus end, Animals, Humans, Autistic Disorder, MESH: Mice, progenitors, MESH: Humans, MESH: Gene Knockdown Techniques, eye diseases, MESH: Cerebellum, MESH: Cerebral Cortex, MESH: Microtubule-Associated Proteins, 030104 developmental biology, GPR56, HEK293 Cells, Memo1, sense organs, 030217 neurology & neurosurgery, corticogenesis
Abstract: International audience; Polarized, non-overlapping, regularly spaced, tiled organization of radial glial cells (RGCs) serves as a framework to generate and organize cortical neuronal columns, layers, and circuitry. Here, we show that mediator of cell motility 1 (Memo1) is a critical determinant of radial glial tiling during neocortical development. Memo1 deletion or knockdown leads to hyperbranching of RGC basal processes and disrupted RGC tiling, resulting in aberrant radial unit assembly and neuronal layering. Memo1 regulates microtubule (MT) stability necessary for RGC tiling. Memo1 deficiency leads to disrupted MT minus-end CAMSAP2 distribution, initiation of aberrant MT branching, and altered polarized trafficking of key basal domain proteins such as GPR56, and thus aberrant RGC tiling. These findings identify Memo1 as a mediator of RGC scaffold tiling, necessary to generate and organize neurons into functional ensembles in the developing cerebral cortex.
Published: 2019
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18. BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids

Author: Nathalie Duval, Célia Vaslin, Xavier Baudin, Vanessa Ribes, Youcef El-Mokhtar Frarma, Stéphane Nedelec, Vincent Contremoulins, Tiago Costa Barata, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Bases Génétiques, Moléculaires et Cellulaires du Développement (BGMCD), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Stem cells in neurodevelopment (SCN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ImagoSeine, Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), S.N. and V.C.R. are Institut National de la Santé et de la Recherche Médicale researchers, N.D. is employed by the Institut Pasteur. Work in the lab of V.R. is supported by a Centre National pour la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale ATIP-AVENIR program, as well as by a Ligue Nationale Contre le Cancer grant (PREAC2016.LCC). Studies in the lab of S.N. are funded by an Institut National de la Santé et de la Recherche Médicale ATIP-AVENIR program co-sponsored by the Association Française contre les Myopathies (AFM-telethon) and a chair of excellence of the Laboratoire d'Excellence de Biologie pour la Psychiatrie (Bio-Psy) (11-LABX-0035)., ANR-11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Duval, Nathalie, Laboratoire de Psychiatrie Biologique - - BIOPSY2011 - ANR-11-LABX-0035 - LABX - VALID, and Institut du Fer à Moulin (UMR-S 1270)
Subjects: Organoid, MESH: Signal Transduction, [SDV]Life Sciences [q-bio], MESH: Bone Morphogenetic Protein 4, MESH: Neurons, Smad Proteins, SMAD, Bone Morphogenetic Protein 4, MESH: Organoids, Pluripotent stem cells differentiation, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, MESH: Animals, Induced pluripotent stem cell, Cells, Cultured, Neurons, 0303 health sciences, Neural crest, Gene Expression Regulation, Developmental, Cell Differentiation, Relay and associating spinal dorsal interneurons, MESH: Interneurons, Cell biology, [SDV] Life Sciences [q-bio], Organoids, Patterning, medicine.anatomical_structure, Neural Crest, embryonic structures, MESH: Spine, Signal Transduction, MESH: Cells, Cultured, Self-organization, MESH: Cell Differentiation, Cell type, Neural Tube, animal structures, Induced Pluripotent Stem Cells, Cell fate determination, Biology, MESH: Induced Pluripotent Stem Cells, Bone morphogenetic protein, MESH: Neural Tube, 03 medical and health sciences, Interneurons, Bone morphogenetic proteins, medicine, Animals, Humans, Cell Lineage, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, Neural tube, MESH: Embryo, Mammalian, MESH: Smad Proteins, MESH: Cell Lineage, Embryo, Mammalian, MESH: Neural Crest, In vitro, Spine, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Bone Morphogenetic Proteins (BMP) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity invivo, whether this is sufficient for pattern formation invitrois unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cells derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species specific tempo of neural differentiation. Together the study describes efficient methods to generate patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.
Published: 2019
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19. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

Author: Jacques L. Michaud, Jessica Sebastian, Hanrong Wu, Dick Lindhout, Karla Manzano-Vargas, Nuwan C. Hettige, Ingrid M. Wentzensen, Huashan Peng, Amy Crunk, Heika Silviera, Malvin Jefri, Henry Houlden, Fadi F. Hamdan, Zahia Aouabed, Stephanie Efthymiou, Xin Zhang, Renske Oegema, Arnaud Tanti, Jerry Vockley, Gustavo Turecki, Julien van Gils, Amber G. Begtrup, Christina Nassif, Gunnar Houge, Naomichi Matsumoto, Thomas Bourgeron, Jean-François Théroux, Emily Fassi, Noriko Miyake, Robert D. Nicholls, Jose E. Martinez, Kristin Herman, Lilit Antonyan, Philippe M. Campeau, Margaret G. Au, Dominic Nelson, Vincenzo Salpietro, Scott C. Bell, Pierre Priam, Joshua L. Deignan, Gregory M. Cooper, Rune Østern, Han G. Brunner, Dagmar Huhle, Amy Goldstein, John M. Graham, Christine Coubes, Koen L.I. van Gassen, Tabib Dabir, Maria Hafström, Simon Gravel, Sophie Ehresmann, Elsa Rossignol, Ilaria Kolobova, Walla Al-Hertani, Julie A. Lessard, Lionel Carmant, Sonja Martin, Richard Delorme, Carl Ernst, Jolien S. Klein Wassink-Ruiter, Naguib Mechawar, Yoshio Makita, Candice R. Finnila, Rami Abou Jamra, Anne Lortie, Justine Rousseau, Sarju G. Mehta, Lina Ghaloul-Gonzalez, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, McGill University = Université McGill [Montréal, Canada], Université de Montréal (UdeM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), GeneDx [Gaithersburg, MD, USA], University of California [Davis] (UC Davis), University of California, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Calgary, UCL, Institute of Neurology [London], Yokohama City University (YCU), Asahikawa Medical College, Trondheim University, Haukeland University Hospital, University of Bergen (UiB), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Groningen [Groningen], University Medical Center Groningen [Groningen] (UMCG), Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Belfast City Hospital, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HudsonAlpha Institute for Biotechnology [Huntsville, AL], Children’s Rehabilitation Service [Mobile, AL] (CRS), Children's Rehabilitation Service [Montgomery, AL] (CRS), University Medical Center [Utrecht], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), University Hospital Leipzig, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cedars-Sinai Medical Center, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), We acknowledge funding by FRQS doctoral (S.B.), Indonesian Endowment Fund for Education PhD award (M.J.), CONACYT (Mexico) and MITACS (K.M.V.), Genome Canada and Génome Québec (J.L.M. and E.R.), Canada Research Chairs program (G.T. and C.E.), AMED, MEXT, JST, MHLW, and Takeda Science Foundation (N. Matsumoto), and CIHR grant (C.E. and P.M.C.)., University of California (UC), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Radboud University [Nijmegen], and Faculteit Medische Wetenschappen/UMCG
Subjects: 0301 basic medicine, Male, PROTEIN EXPRESSION, Chromosomal Proteins, Non-Histone, Mutant, MESH: Neurons, 0302 clinical medicine, SYNAPTIC PLASTICITY, MESH: Child, Genetics(clinical), Global developmental delay, TRANSCRIPTION, Child, Genetics (clinical), ACTL6B, genetic engineering, intellectual disability, neurodevelopment, seizure, stem cells, Genetics, Neurons, SWI/SNF COMPLEX, MESH: Infant, Hypotonia, Neural stem cell, Chromatin, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Young Adult, MESH: Epilepsy, Child, Preschool, Female, medicine.symptom, Adult, MESH: Mutation, DISORDERS, Induced Pluripotent Stem Cells, Biology, MESH: Induced Pluripotent Stem Cells, MESH: Actins, MESH: Dendrites, Chromatin remodeling, Article, MESH: Chromatin, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, MESH: Chromosomal Proteins, Non-Histone, medicine, Journal Article, Humans, CHROMATIN REMODELING COMPLEX, Progenitor cell, Loss function, MESH: Neurodevelopmental Disorders, MESH: Humans, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Child, Preschool, COFFIN-SIRIS SYNDROME, MEMORY, Infant, MESH: Adult, Dendrites, GENE, MESH: Male, Actins, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, OLIGODENDROCYTE, Neuron, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: International audience; We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
Published: 2019
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20. Structural and functional connections between the median and the ventrolateral preoptic nucleus. : The MnPO-VLPO pathway

Author: Walter, Augustin, Van Der Spek, Lorijn, Hardy, Eléonore, Bemelmans, Alexis-Pierre, Rouach, Nathalie, Rancillac, Armelle, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (Inserm) and Collège de France.
Subjects: MESH: Axons, VLPO, MEA, MESH: Neuroanatomical Tract-Tracing Techniques, MESH: Neural Pathways, MESH: Neurons, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Sleep-promoting neuron, MESH: Male, MESH: Mice, Inbred C57BL, MESH: Preoptic Area, NREM sleep, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], field recordings, MnPO
Abstract: International audience; The median preoptic nucleus (MnPO) and the ventrolateral preoptic nucleus (VLPO) are two brain structures that contain neurons essential for promoting non-rapid eye movement (NREM) sleep. However, their connections are still largely unknown. Here, we describe for the first time a slice preparation with an oblique coronal slicing angle at 70° from the horizontal in which their connectivity is preserved. Using the in vivo iDISCO method following viral infection of the MnPO or ex vivo biocytin crystal deposition in the MnPO of mouse brain slices, we revealed a strong axonal pathway from the MnPO to the VLPO. Then, to further explore the functionality of these projections, acute 70° slices were placed on multielectrode arrays (MEAs) and electrical stimulations were performed near the MnPO. Recordings of the signals propagation throughout the slices revealed a preferential pathway from the MnPO to the VLPO. Finally, we performed an input-output curve of field responses evoked by stimulation of the MnPO and recorded in the VLPO. We found that field responses were inhibited by GABAA receptor antagonist, suggesting that afferent inputs from the MnPO activate VLPO neuronal networks by disinhibition.
Published: 2019
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21. Correlative cryo-electron microscopy reveals the structure of TNTs in neuronal cells

Author: Anna Sartori-Rupp, Jacomina Krijnse-Locker, Anna Pepe, Diégo Cordero Cervantes, Elise Delage, Chiara Zurzolo, Karine Gousset, Christine Schmitt, Simon Corroyer-Dulmont, Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Trafic membranaire et Pathogénèse, California State University [Fresno] (Fresno State), We acknowledge the Ultrastructural Bio-Imaging facility at Institut Pasteur, member of the national infrastructure France-Bio-Imaging (FBI) supported by the French National Research Agency (ANR-10-INBS-04) and IBISA.This work was supported by grants from the Agence Nationale de Recherche (JPND Neutargets: ANR-14-JPCD-0002-01 and ANR-16 CE160019-01 NEUROTUNN), and the Equipe FRM (Fondation Recherche Médicale) 2014 (DEQ20140329557) to C.Z. D.C.Cwas supported by the Pasteur—Paris University (PPU) International PhD Program. A.P.was supported by fellowships from France Parkinson and the Fondazione ErmenegildoZegna., We thank Seng Zhu for image analysis technical expertize and Christel Brou for valuable manuscript comments. We also gratefully acknowledge Gerard Péhau-Arnaudet (Ultrapole, Institut Pasteur) for his help in setting up freezing conditions of CAD cells during early stages of the project, and Remi Blanc from Amira (FEI, Thermo Fischer Scientific) for the automated segmentation of actin in Fig. 6 using the XTracing—Filament detection module. We thank the equipment excellence CACSICE for providing the Falcon II direct electron detector, ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-14-JPCD-0002,Neutargets,Targeting the propagation of pathogenic protein assemblies in neurodegenerative disease(2014), ANR-16-CE16-0019,Neurotunn,Role des nanotubes membranaires dans la propagation d'agrégats protéiques impliqués dans les maladie neurodégénératives(2016), Sartori-Rupp, A., Cordero Cervantes, D., Pepe, A., Gousset, K., Delage, E., Corroyer-Dulmont, S., Schmitt, C., Krijnse-Locker, J., Zurzolo, C., and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Cryo-electron microscopy, Cell, MESH: Neurons, General Physics and Astronomy, 02 engineering and technology, Mice, Catecholamines, Microscopy, MESH: Animals, lcsh:Science, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Neurons, Multidisciplinary, Cell Surface Extension, Chemistry, MESH: Cell Surface Extensions, 021001 nanoscience & nanotechnology, medicine.anatomical_structure, Catecholamine, MESH: Cryoelectron Microscopy, 0210 nano-technology, Human, Science, MESH: Biological Transport, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Organelle, medicine, MESH: Catecholamines, Animals, Humans, MESH: Mice, Actin, Organelles, MESH: Humans, Animal, Intercellular transport, Cryoelectron Microscopy, Biological Transport, General Chemistry, Neuron, MESH: Cell Line, Multicellular organism, 030104 developmental biology, Cytoplasm, Biophysics, lcsh:Q, Cell Surface Extensions, MESH: Organelles
Abstract: The orchestration of intercellular communication is essential for multicellular organisms. One mechanism by which cells communicate is through long, actin-rich membranous protrusions called tunneling nanotubes (TNTs), which allow the intercellular transport of various cargoes, between the cytoplasm of distant cells in vitro and in vivo. With most studies failing to establish their structural identity and examine whether they are truly open-ended organelles, there is a need to study the anatomy of TNTs at the nanometer resolution. Here, we use correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structural organization of neuronal TNTs. Our data indicate that they are composed of a bundle of open-ended individual tunneling nanotubes (iTNTs) that are held together by threads labeled with anti-N-Cadherin antibodies. iTNTs are filled with parallel actin bundles on which different membrane-bound compartments and mitochondria appear to transfer. These results provide evidence that neuronal TNTs have distinct structural features compared to other cell protrusions., The architecture of functional TNTs is still under debate. Here, the authors combine correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structure of TNTs in neuronal cells, showing that they form structures that are distinct form other membrane protrusions.
Published: 2019
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22. A transgenic mouse expressing CHMP2Bintron5mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia

Author: Frédérique René, Aurelia Vernay, Thiebault Lequeu, Robin Waegaert, Béatrice Blot, François Sellal, Jean-Philippe Loeffler, Rémy Sadoul, Valerie Risson, Sylvie Dirrig-Grosch, Ludivine Therreau, Laurent Schaeffer, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire Ressources et Recherche [Strasbourg] (CMRR Strasbourg), CHU Strasbourg, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Dieterle, Stéphane
Subjects: 0301 basic medicine, MESH: Introns, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Endosomal Sorting Complexes Required for Transport, Mice, [SCCO]Cognitive science, 0302 clinical medicine, C9orf72, MESH: Behavior, Animal, ALS‐FTD, MESH: Animals, MESH: Nerve Tissue Proteins, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, Genetics (clinical), Neurons, Denervation, Behavior, Animal, Neurodegeneration, neurodegeneration, General Medicine, Anatomy, Sciatic Nerve, MESH: Gene Expression Regulation, Motor coordination, [SDV] Life Sciences [q-bio], MESH: Sciatic Nerve, medicine.anatomical_structure, Frontotemporal Dementia, Frontotemporal dementia, autophagy, MESH: Axons, MESH: Mutation, MESH: Mice, Transgenic, C9ORF72, MESH: Frontotemporal Dementia, Mice, Transgenic, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Genetics, medicine, Animals, Humans, MESH: Mice, Molecular Biology, MESH: Humans, Endosomal Sorting Complexes Required for Transport, Amyotrophic Lateral Sclerosis, [SCCO] Cognitive science, Charged multivesicular body protein 2B, medicine.disease, Spinal cord, Axons, Introns, 030104 developmental biology, Gene Expression Regulation, Mutation, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2Bintron5 mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5 As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5 in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.
Published: 2016
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23. The SONATA data format for efficient description of large-scale network models

Author: Salvador Dura-Bernal, Jean-Denis Courcol, Arseny V. Povolotsky, Michael Gevaert, Sergey L. Gratiy, Padraig Gleeson, James G. King, Anton Arkhipov, Adrien Devresse, Eilif Muller, Werner Van Geit, Benjamin Dichter, Juan Hernando, Judit Planas, Yazan N. Billeh, Kael Dai, Andrew P. Davison, Allen Institute for Brain Science [Seattle, WA, USA], Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), SUNY Downstate Medical Center, State University of New York (SUNY), Nathan S. Kline Institute for Psychiatric Research (NKI), New York State Office of Mental Health, Department of Neuroscience, Physiology & Pharmacology, University College of London [London] (UCL), Department of Neurosurgery [Stanford], Stanford Medicine, Stanford University-Stanford University, and Biological Systems and Engineering
Subjects: 0301 basic medicine, Databases, Factual, Physiology, Computer science, network models, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Distributed computing, MESH: Neurons, Nervous System, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Biology (General), MESH: Brain Mapping, Network model, Neurons, Brain Mapping, 0303 health sciences, Computational model, Neuronal Morphology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Ecology, Application programming interface, Simulation and Modeling, Physics, Brain, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Electrophysiology, MESH: Reproducibility of Results, Computational Theory and Mathematics, Modeling and Simulation, Physical Sciences, Scalability, MESH: Programming Languages, Cellular Types, Anatomy, Model building, Network Analysis, Algorithms, Research Article, MESH: Computational Biology, Network analysis, Computer and Information Sciences, Biophysical Simulations, Neural Networks, QH301-705.5, Models, Neurological, Biophysics, Neurophysiology, MESH: Algorithms, Research and Analysis Methods, MESH: Brain, MESH: Software, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Computer Simulation, MESH: Models, Neurological, Genetics, Humans, Computer Simulation, Molecular Biology, Ecology, Evolution, Behavior and Systematics, data format, 030304 developmental biology, Flexibility (engineering), MESH: Humans, Scale (chemistry), Neurosciences, Biology and Life Sciences, Computational Biology, Reproducibility of Results, Cell Biology, MESH: Neurosciences, MESH: Databases, Factual, Visualization, SONATA, 030104 developmental biology, Cellular Neuroscience, Synapses, Open network architecture, Programming Languages, Software, 030217 neurology & neurosurgery, Neuroscience
Abstract: Increasing availability of comprehensive experimental datasets and of high-performance computing resources are driving rapid growth in scale, complexity, and biological realism of computational models in neuroscience. To support construction and simulation, as well as sharing of such large-scale models, a broadly applicable, flexible, and high-performance data format is necessary. To address this need, we have developed the Scalable Open Network Architecture TemplAte (SONATA) data format. It is designed for memory and computational efficiency and works across multiple platforms. The format represents neuronal circuits and simulation inputs and outputs via standardized files and provides much flexibility for adding new conventions or extensions. SONATA is used in multiple modeling and visualization tools, and we also provide reference Application Programming Interfaces and model examples to catalyze further adoption. SONATA format is free and open for the community to use and build upon with the goal of enabling efficient model building, sharing, and reproducibility., Author summary Neuroscience is experiencing a rapid growth of data streams characterizing composition, connectivity, and activity of brain networks in ever increasing details. Data-driven modeling will be essential to integrate these multimodal and complex data into predictive simulations to advance our understanding of brain function and mechanisms. To enable efficient development and sharing of such large-scale models utilizing diverse data types, we have developed the Scalable Open Network Architecture TemplAte (SONATA) data format. The format represents neuronal circuits and simulation inputs and outputs via standardized files and provides much flexibility for adding new conventions or extensions. SONATA is already supported by several popular tools for model building, simulations, and visualization. It is free and open for everyone to use and build upon and will enable increased efficiency, reproducibility, and scientific exchange in the community.
Published: 2020
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24. Potential pathogenic mechanisms underlying Fragile X Tremor Ataxia Syndrome: RAN translation and/or RNA gain-of-function?

Author: Chantal Sellier, Renate K. Hukema, Rob Willemsen, Manon Boivin, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Dieterle, Stéphane, and Clinical Genetics
Subjects: 0301 basic medicine, MESH: Ataxia, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Tremor, Fragile X Mental Retardation Protein, 0302 clinical medicine, Tremor, MESH: Trinucleotide Repeat Expansion, MESH: Animals, Genetics (clinical), Neurons, Fragile X Tremor/Ataxia Syndrome, Brain, General Medicine, 3. Good health, Antisense RNA, [SDV] Life Sciences [q-bio], Gain of Function Mutation, Intention tremor, medicine.symptom, MESH: Fragile X Syndrome, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, MESH: Ubiquitin, Biology, MESH: Fragile X Mental Retardation Protein, 03 medical and health sciences, MESH: Brain, Atrophy, RAN translation, Genetics, medicine, Animals, Humans, MESH: Gain of Function Mutation, MESH: Humans, Ubiquitin, RNA, medicine.disease, FMR1, nervous system diseases, MESH: Astrocytes, Disease Models, Animal, 030104 developmental biology, Astrocytes, Fragile X Syndrome, Gait Ataxia, FXTAS, MESH: Disease Models, Animal, Trinucleotide Repeat Expansion, RNA gain-of-function, Neuroscience, Microsatellite expansion, 030217 neurology & neurosurgery
Abstract: International audience; Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease caused by an expansion of 55-200 CGG repeats located in the FMR1 gene. The main clinical and neuropathological features of FXTAS are progressive intention tremor and gait ataxia associated with brain atrophy, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in both neurons and astrocytes. At the molecular level, FXTAS is characterized by increased expression of FMR1 sense and antisense RNA containing expanded CGG or GGC repeats, respectively. Here, we discuss the putative molecular mechanisms underlying FXTAS and notably recent reports that expanded CGG and GGC repeats may be pathogenic through RAN translation into toxic proteins.
Published: 2018
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25. High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Author: Medina-Cano, Daniel, Ucuncu, Ekin, Nguyen, Lam Son, Nicouleau, Michael, Lipecka, Joanna, Bizot, Jean-Charles, Thiel, Christian, Foulquier, François, Lefort, Nathalie, Faivre-Sarrailh, Catherine, Colleaux, Laurence, Guerrera, Ida Chiara, Cantagrel, Vincent, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de chimie et procédés pour l'énergie, l'environnement et la santé (ICPEES), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), PRA, Fanny, Mécanismes développementaux des anomalies structurelles cérébelleuses - - SCD-Mec2016 - ANR-16-CE12-0005 - AAPG2016 - VALID, ERA-NET rare disease research implementing IRDiRC objectives - E-Rare-3 - - H20202014-12-01 - 2019-11-30 - 643578 - VALID, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Key-Obs, ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), and Centre de Psychiatrie et Neurosciences (U894)
Subjects: Glycosylation, MESH: Immunoglobulins, [SDV]Life Sciences [q-bio], MESH: Neurons, N-glycosylation, MESH: Unfolded Protein Response, MESH: Mice, Knockout, neuroscience, Purkinje Cells, MESH: Axon Guidance, Neural Pathways, cell biology, MESH: Animals, Biology (General), Mice, Knockout, Neurons, neuronal migration, MESH: Proteomics, Srd5a3, Cell Differentiation, MESH: Glycosylation, MESH: Motor Activity, Axon Guidance, MESH: Reproducibility of Results, MESH: Cell Adhesion Molecules, Medicine, lipids (amino acids, peptides, and proteins), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Membrane Proteins, Research Article, MESH: Cell Differentiation, MESH: Mutation, animal structures, cerebellum, QH301-705.5, Science, Induced Pluripotent Stem Cells, Immunoglobulins, MESH: Cytoplasmic Granules, Motor Activity, MESH: Induced Pluripotent Stem Cells, Cytoplasmic Granules, MESH: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, MESH: Cell Adhesion, MESH: Purkinje Cells, proteomics, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Polysaccharides, Animals, human, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], mouse, MESH: Neural Pathways, Cell Membrane, Membrane Proteins, Reproducibility of Results, cell adhesion, MESH: Cerebellum, carbohydrates (lipids), MESH: Polysaccharides, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Gene Deletion, Protein N-glycosylation, Mutation, Unfolded Protein Response, Cell Adhesion Molecules, Gene Deletion, MESH: Cell Membrane, congenital disorders of glycosylation
Abstract: International audience; Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.
Published: 2018
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26. [Restoration of damaged cortical pathways by neural grafting]

Author: Ballout, Nissrine, Péron, Sophie, Gaillard, Afsaneh, Laboratoire de neurosciences expérimentales et cliniques (LNEC), and Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Neurons, MESH: Nerve Regeneration, MESH: Humans, [SDV]Life Sciences [q-bio], MESH: Neurons, Motor Cortex, MESH: Adult, MESH: Motor Cortex, Nerve Regeneration, Nerve Fibers, MESH: Nerve Net, Brain Injuries, MESH: Brain Injuries, Animals, Humans, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nerve Net, MESH: Nerve Fibers
Abstract: International audience; The motor cortex plays a central role in the control, planning, and execution of voluntary motor commands in mammals. The loss of cortical neurons is a common feature of many neuropathological conditions such as traumatic and ischemic lesions or several neurodegenerative diseases. Cell transplantation presents a promising therapeutic strategy to overcome the limited abilities of axonal regrowth and spontaneous regeneration of the adult central nervous system. In this review, we will present a historical review of brain transplantation and the current state of research in the field of cortical transplantation.; Le cortex moteur joue un rôle central dans le contrôle, la planification et l’exécution des commandes motrices volontaires chez les mammifères et la perte de neurones corticaux est une caractéristique commune à de nombreuses conditions neuropathologiques, comme les lésions traumatiques, ischémiques ou certaines maladies neurodégénératives. Afin de pallier les capacités limitées de régénération spontanée des neurones du système nerveux central adulte, des stratégies de remplacement cellulaire, par transplantation de tissu immature, présentent un potentiel prometteur. Dans cette revue, nous présenterons un rappel historique de la transplantation au niveau du cerveau et l’état actuel de la recherche dans le domaine de la transplantation corticale.
Published: 2018
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27. How Does a Memory Find Its Neurons?

Author: Christoph Schmidt-Hieber, Institut Pasteur [Paris], This work was supported by a grant from the ERC (StG 678790 NEWRON)., European Project: 678790,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,NEWRON(2016), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Neurons, MESH: Hippocampus, MESH: Neurons, Hippocampus, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Memory, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Memory, Psychology, 030217 neurology & neurosurgery
Abstract: This article comments on the Hypothesis paper by Thiago F. A. França and José M. Monserrat, https://doi.org/10.1002/bies.201800068; International audience; How does the brain store and recall memories? We have long known that a brain region called the hippocampus is critical for processing episodic memories. More recently, targeted manipulation of the activity of specific hippocampal neurons in rodents has suggested that memories are encoded by the firing of defined groups of hippocampal neurons, so-called cellular engrams. In the current issue of BioEssays, FranS ca and Monserrat discuss a key question that has puzzled the field for a while: Among the millions of neurons in the mammalian hippocam-pus, how is a subset recruited into a memory engram? [1] Basic neurophysiology teaches us that two factors largely determine whether a neuron is active: On the one hand, each neuron is excited or inhibited by thousands of synaptic inputs that convey information both about the outside world, and about ongoing processing of information in the brain. On the other hand, how these synaptic inputs will affect the activity of a neuron depends on its excitability, which in turn is determined by factors such as its morphological and biophysical properties. A straightforward prediction, then, is that an engram is uniquely associated with a specific memory: A given set of sensory stimuli, let's say the odors, colors, and sounds experienced during memory formation, should recruit a given set of neurons-an engram-that is largely predetermined by synaptic connectivity and excitability. Similarly, activating an engram should recall its associated memory, but not others. Recent experiments in rodents have challenged these straightforward predictions: manipulating the excitability of neurons suggests that there is some redundancy in the hippocampal code, as inhibiting putative future engram cells during memory formation does not inhibit learning of a new memory. [2] Instead, it appears as if the memory could simply be stored in a different population of neurons. From these experiments, one might conclude that hippocampal neurons are stochastically recruited into engrams, and that their initial synaptic wiring plays only a minor role in their selection. [3] How can the straightforward predictions from basic neuro-physiology be reconciled with the seemingly stochastic composition of engrams? FranS ca and Monserrat invoke insights into C. elegans circuits to argue that individual neurons can represent multiple dimensions of both external and internal variables, most of which escape our observation. While we typically test the purely spatial aspect of memories in rodents, we have relatively little experimental control over variables other than physical space, such as an animal's current goal, attention, or more fundamental sensations such as hunger or thirst. Furthermore, the authors argue that once there is some synaptic distance between the primary sensory inputs and the neurons of interest, these dimensions will be increasingly abstract. Finally, they propose that the apparent redundancy of the code can be explained by the insight that while stimulating two non-overlapping populations of engram neurons may have the same behavioral effect, that does not necessarily mean that the same memory was recalled, as recalling even very different memories may evoke the same behavioral output. Thus, they conclude that the wiring and excitability of hippocampal neurons provides a template for memory allocation, and that the seemingly stochastic nature of engrams can be explained by the notion that hippocampal neurons represent multiple, abstract dimensions. This is a timely review on a highly interesting topic, and the authors make some novel and creative points about memory allocation. Further work will be required to show whether the striking temporal dynamics of hippocampal representations, [4] which appears to be at odds with engrams determined by hard wiring, are indeed a consequence of varying attentional levels, or whether additional mechanisms such as synaptic turnover may contribute to engram formation. An important conclusion from their work is that we need better behavioral tasks for animals used in hippocampal research, which are typically rodents. A simple behavior, as tested by a dichotomic go/no-go task, may be the end point of widely different cognitive processes. This redundancy could be reduced if more complex behaviors including multiple choices were tested. More sophisticated behavioral tasks, together with improved control and monitoring of external stimuli and behavioral variables, may therefore disambiguate the effects of stimulating different engrams, and help understand how hippocampal neurons are recruited into memory circuits.
Published: 2018
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28. Restauration des voies corticales lésées par greffe de neurones

Author: Nissrine Ballout, Sophie Péron, Afsaneh Gaillard, Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), and BALLION, Bérangère
Subjects: 0301 basic medicine, MESH: Nerve Regeneration, [SDV]Life Sciences [q-bio], Central nervous system, MESH: Neurons, MESH: Motor Cortex, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Cell transplantation, medicine, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Nerve Fibers, Therapeutic strategy, MESH: Humans, business.industry, Regeneration (biology), MESH: Adult, General Medicine, Cortical neurons, Transplantation, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, MESH: Nerve Net, Neural grafting, MESH: Brain Injuries, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience, 030217 neurology & neurosurgery, Motor cortex
Abstract: The motor cortex plays a central role in the control, planning, and execution of voluntary motor commands in mammals. The loss of cortical neurons is a common feature of many neuropathological conditions such as traumatic and ischemic lesions or several neurodegenerative diseases. Cell transplantation presents a promising therapeutic strategy to overcome the limited abilities of axonal regrowth and spontaneous regeneration of the adult central nervous system. In this review, we will present a historical review of brain transplantation and the current state of research in the field of cortical transplantation., Le cortex moteur joue un rôle central dans le contrôle, la planification et l’exécution des commandes motrices volontaires chez les mammifères et la perte de neurones corticaux est une caractéristique commune à de nombreuses conditions neuropathologiques, comme les lésions traumatiques, ischémiques ou certaines maladies neurodégénératives. Afin de pallier les capacités limitées de régénération spontanée des neurones du système nerveux central adulte, des stratégies de remplacement cellulaire, par transplantation de tissu immature, présentent un potentiel prometteur. Dans cette revue, nous présenterons un rappel historique de la transplantation au niveau du cerveau et l’état actuel de la recherche dans le domaine de la transplantation corticale.
Published: 2018
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29. Neuronal Mitophagy: Lessons from a Pathway Linked to Parkinson's Disease

Author: Olga Corti, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Aging, Parkinson's disease, PINK1 and Parkin-dependent mitochondrial quality control, MESH: Mitochondria, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mitochondrial stress, MESH: Mitophagy, MESH: Neurons, PINK1, Mitochondrion, Biology, Toxicology, Parkin, 03 medical and health sciences, 0302 clinical medicine, Lysosome, Mitophagy, medicine, Autophagy, MESH: Autophagy, Animals, Humans, MESH: Animals, Growth cone, Cells, Cultured, Neurons, MESH: Humans, General Neuroscience, Fluorescent mitophagy reporters, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Parkinson Disease, medicine.disease, Mitochondria, 030104 developmental biology, medicine.anatomical_structure, Parkinson’s disease, Neuroscience, 030217 neurology & neurosurgery, MESH: Parkinson Disease, MESH: Cells, Cultured
Abstract: International audience; Neurons are specialized cells with complex and extended architecture and high energy requirements. Energy in the form of adenosine triphosphate, produced essentially by mitochondrial respiration, is necessary to preserve neuronal morphology, maintain resting potential, fire action potentials, and ensure neurotransmission. Pools of functional mitochondria are required in all neuronal compartments, including cell body and dendrites, nodes of Ranvier, growth cones, axons, and synapses. The mechanisms by which old or damaged mitochondria are removed and replaced in neurons remain to be fully understood. Mitophagy has gained considerable interest since the discovery of familial forms of Parkinson's disease caused by dysfunction of PINK1 and Parkin, two multifunctional proteins cooperating in the regulation of this process. Over the past 10 years, the molecular mechanisms by which PINK1 and Parkin jointly promote the degradation of defective mitochondria by autophagy have been dissected. However, our understanding of the relevance of mitophagy to mitochondrial homeostasis in neurons remains poor. Insight has been recently gained thanks to the development of fluorescent reporter systems for tracking mitochondria in the acidic compartment of the lysosome. Using these tools, mitophagy events have been visualized in primary neurons in culture and in vivo, under basal conditions and in response to toxic insults. Despite these advances, whether PINK1 and Parkin play a major role in promoting neuronal mitophagy under physiological conditions in adult animals and during aging remains a matter of debate. Future studies will have to clarify in how far dysfunction of neuronal mitophagy is central to the pathophysiology of Parkinson's disease.
Published: 2018
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30. The VAMP‐associated protein VAPB is required for cardiac and neuronal pacemaker channel function

Author: Nicole, Silbernagel, Magdalena, Walecki, Martin K-H, Schäfer, Mirjam, Kessler, Mehrnoush, Zobeiri, Susanne, Rinné, Aytug K, Kiper, Marlene A, Komadowski, Kirsty S, Vowinkel, Konstantin, Wemhöner, Lisa, Fortmüller, Marcus, Schewe, Amalia M, Dolga, Jelena, Scekic-Zahirovic, Lina A, Matschke, Carsten, Culmsee, Thomas, Baukrowitz, Laurent, Monassier, Nina D, Ullrich, Luc, Dupuis, Steffen, Just, Thomas, Budde, Larissa, Fabritz, Niels, Decher, Phillips University [Marburg, Germany] (PU), Universitätsklinikum Ulm - University Hospital of Ulm, University of Münster, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Christian-Albrechts University of Kiel, Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (LPTNC), Université de Strasbourg (UNISTRA), Universität Heidelberg [Heidelberg], Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospitals Birmingham [Birmingham, Royaume-Uni], University of Birmingham [Birmingham], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), and Dieterle, Stéphane
Subjects: Pacemaker, Artificial, Embryo, Nonmammalian, MESH: Vesicular Transport Proteins, MESH: Rats, [SDV]Life Sciences [q-bio], Vesicular Transport Proteins, MESH: Neurons, MESH: Carrier Proteins, MESH: Rats, Sprague-Dawley, MESH: Mice, Knockout, Rats, Sprague-Dawley, HCN channels, Mice, Xenopus laevis, cardiac arrhythmia, MESH: Xenopus laevis, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Animals, Humans, MESH: Animals, MESH: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, MESH: Zebrafish, MESH: Mice, Zebrafish, Mice, Knockout, Neurons, MESH: Humans, Research, Membrane Proteins, MESH: Embryo, Nonmammalian, Heart, MESH: Ion Channel Gating, Rats, [SDV] Life Sciences [q-bio], MESH: Heart, MESH: HeLa Cells, MESH: Pacemaker, Artificial, Female, MESH: Membrane Proteins, ALS, Carrier Proteins, Ion Channel Gating, MESH: Female, HeLa Cells
Abstract: International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels encode neuronal and cardiac pacemaker currents. The composition of pacemaker channel complexes in different tissues is poorly understood, and the presence of additional HCN modulating subunits was speculated. Here we show that vesicle-associated membrane protein-associated protein B (VAPB), previously associated with a familial form of amyotrophic lateral sclerosis 8, is an essential HCN1 and HCN2 modulator. VAPB significantly increases HCN2 currents and surface expression and has a major influence on the dendritic neuronal distribution of HCN2. Severe cardiac bradycardias in VAPB-deficient zebrafish and VAPB-/- mice highlight that VAPB physiologically serves to increase cardiac pacemaker currents. An altered T-wave morphology observed in the ECGs of VAPB-/- mice supports the recently proposed role of HCN channels for ventricular repolarization. The critical function of VAPB in native pacemaker channel complexes will be relevant for our understanding of cardiac arrhythmias and epilepsies, and provides an unexpected link between these diseases and amyotrophic lateral sclerosis.-Silbernagel, N., Walecki, M., Schäfer, M.-K. H., Kessler, M., Zobeiri, M., Rinné, S., Kiper, A. K., Komadowski, M. A., Vowinkel, K. S., Wemhöner, K., Fortmüller, L., Schewe, M., Dolga, A. M., Scekic-Zahirovic, J., Matschke, L. A., Culmsee, C., Baukrowitz, T., Monassier, L., Ullrich, N. D., Dupuis, L., Just, S., Budde, T., Fabritz, L., Decher, N. The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function.
Published: 2018
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31. Maximum-entropy models reveal the excitatory and inhibitory correlation structures in cortical neuronal activity

Author: Ulisse Ferrari, Trang-Anh Nghiem, Bartosz Telenczuk, Olivier Marre, Alain Destexhe, Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PERIGNON, Alain, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Entropy, MESH: Neurons, Action Potentials, 0302 clinical medicine, Cortex (anatomy), Premovement neuronal activity, monkey cortex, MESH: Animals, MESH: Action Potentials, Slow-wave sleep, Physics, Cerebral Cortex, Neurons, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Principle of maximum entropy, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Condensed Matter - Disordered Systems and Neural Networks, MESH: Entropy, medicine.anatomical_structure, Cerebral cortex, Excitatory postsynaptic potential, Wakefulness, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurons and Cognition (q-bio.NC), human cortex, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Models, Neurological, FOS: Physical sciences, Inhibitory postsynaptic potential, 03 medical and health sciences, brain states, MESH: Models, Neurological, wakefulness, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Humans, Disordered Systems and Neural Networks (cond-mat.dis-nn), Slow-Wave Sleep, MESH: Cerebral Cortex, 030104 developmental biology, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, Neuroscience, Maximum Entropy models, 030217 neurology & neurosurgery
Abstract: Maximum Entropy models can be inferred from large data-sets to uncover how collective dynamics emerge from local interactions. Here, such models are employed to investigate neurons recorded by multielectrode arrays in the human and monkey cortex. Taking advantage of the separation of excitatory and inhibitory neuron types, we construct a model including this distinction. This approach allows to shed light upon differences between excitatory and inhibitory activity across different brain states such as wakefulness and deep sleep, in agreement with previous findings. Additionally, Maximum Entropy models can also unveil novel features of neuronal interactions, which are found to be dominated by pairwise interactions during wakefulness, but are population-wide during deep sleep. In particular, inhibitory neurons are observed to be strongly tuned to the inhibitory population. Overall, we demonstrate Maximum Entropy models can be useful to analyze data-sets with classified neuron types, and to reveal the respective roles of excitatory and inhibitory neurons in organizing coherent dynamics in the cerebral cortex., Comment: 17 pages, 11 figures (including 5 supplementary)
Published: 2018
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32. Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function

Author: Dorothee Dormann, Stefan Reber, Luc Dupuis, Helena Ederle, Marian Hruska-Plochan, Eva-Maria Hock, Marc-David Ruepp, Florent Laferrière, Zuzanna Maniecka, Lucas Pelkmans, M K Sonu Sahadevan, Tammaryn Lashley, Lauren M. Gittings, Magdalini Polymenidou, Dieterle, Stéphane, Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Bern, Ludwig Maximilian University [Munich] (LMU), UCL, Institute of Neurology [London], Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Universität Bern [Bern], Ludwig-Maximilians-Universität München (LMU), Institute of Neurology [London], King‘s College London, Universität Bern [Bern] (UNIBE), Laferriere, Florent, University of Zurich, and Polymenidou, Magdalini
Subjects: 0301 basic medicine, Cytoplasm, MESH: Hippocampus, Cytoplasmic inclusion, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], MESH: Neurons, Chromosomal translocation, RNA-binding protein, RNA-binding proteins, Hippocampus, Mice, ALS, FTD, FUS, stress granules, nucleocytoplasmic shuttling, Transportin, protein aggregation, MESH: Animals, Amyotrophic lateral sclerosis, Cerebral Cortex, Neurons, Chemistry, MESH: RNA-Binding Protein FUS, Cell biology, [SDV] Life Sciences [q-bio], MESH: HEK293 Cells, Transportin 1, MESH: Cell Nucleus, 610 Medicine & health, Genetics and Molecular Biology, Karyopherins, Transfection, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Stress granule, 1300 General Biochemistry, Genetics and Molecular Biology, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, MESH: Mice, Cell Nucleus, MESH: Humans, MESH: Cytoplasm, MESH: Transfection, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Karyopherins, MESH: Cerebral Cortex, Mice, Inbred C57BL, MESH: Astrocytes, HEK293 Cells, 030104 developmental biology, Hypertonic Stress, Astrocytes, General Biochemistry, RNA-Binding Protein FUS, 11493 Department of Quantitative Biomedicine
Abstract: The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an ex vivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology., Cell Reports, 24 (4), ISSN:2666-3864, ISSN:2211-1247
Published: 2018
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33. A Peptidomic Approach to Characterize Peptides Involved in Cerebellar Cortex Development Leads to the Identification of the Neurotrophic Effects of Nociceptin

Author: Marie-Laure Walet-Balieu, Philippe Chan, Auriane Corbière, David Vaudry, Magali Basille-Dugay, Julie Hardouin, Lebon, Alexis, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-forme de Protéomique PISSARO, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Proteomics, MESH: Receptors, Opioid, Cerebellum, [SDV]Life Sciences [q-bio], MESH: Neurons, Apoptosis, MESH: Amino Acid Sequence, Biochemistry, Nociceptin Receptor, Analytical Chemistry, 0302 clinical medicine, MESH: Opioid Peptides, MESH: Animals, Receptor, Cells, Cultured, Neurons, biology, MESH: Peptides, MESH: Proteomics, Cell Differentiation, [SDV] Life Sciences [q-bio], Nociceptin receptor, medicine.anatomical_structure, Somatostatin, Opioid Peptides, Cerebellar cortex, MESH: Hydrogen Peroxide, Female, Neurotrophin, MESH: Cells, Cultured, MESH: Cell Differentiation, Neuropeptide, 03 medical and health sciences, Cerebellar Cortex, medicine, Animals, Amino Acid Sequence, Nerve Growth Factors, RNA, Messenger, Rats, Wistar, Molecular Biology, MESH: RNA, Messenger, MESH: Cerebellar Cortex, MESH: Nerve Growth Factors, Research, MESH: Apoptosis, Hydrogen Peroxide, MESH: Rats, Wistar, Granule cell, MESH: Cerebellum, MESH: Male, 030104 developmental biology, nervous system, Receptors, Opioid, biology.protein, Peptides, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; The cerebellum is a brain structure involved in motor and cognitive functions. The development of the cerebellar cortex (the external part of the cerebellum) is under the control of numerous factors. Among these factors, neuropeptides including PACAP or somatostatin modulate the survival, migration and/or differentiation of cerebellar granule cells. Interestingly, such peptides contributing to cerebellar ontogenesis usually exhibit a specific transient expression profile with a low abundance at birth, a high expression level during the developmental processes, which take place within the first two postnatal weeks in rodents, and a gradual decline toward adulthood. Thus, to identify new peptides transiently expressed in the cerebellum during development, rat cerebella were sampled from birth to adulthood, and analyzed by a semi-quantitative peptidomic approach. A total of 33 peptides were found to be expressed in the cerebellum. Among these 33 peptides, 8 had a clear differential expression pattern during development, 4 of them i.e. cerebellin 2, nociceptin, somatostatin and VGF [353-372], exhibiting a high expression level during the first two postnatal weeks followed by a significative decrease at adulthood. A focus by a genomic approach on nociceptin, confirmed that its precursor mRNA is transiently expressed during the first week of life in granule neurons within the internal granule cell layer of the cerebellum, and showed that the nociceptin receptor is also actively expressed between P8 and P16 by the same neurons. Finally, functional studies revealed a new role for nociceptin, acting as a neurotrophic peptide able to promote the survival and differentiation of developing cerebellar granule neurons.
Published: 2018
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34. Non-linear auto-regressive models for cross-frequency coupling in neural time series

Author: Virginie van Wassenhove, Yves Grenier, Alexandre Gramfort, Laetitia Grabot, Lucille Tallot, Tom Dupré la Tour, Valérie Doyère, Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie cognitive (LCogn), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimagerie cognitive (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Signal, Statistique et Apprentissage (S2A), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT), Département Images, Données, Signal (IDS), Télécom ParisTech, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria), Institut Mines-Télécom [Paris] (IMT)-Télécom Paris, Institut des Neurosciences Paris-Saclay (NeuroPSI), Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ANR-16-CE37-0004,AutoTime,Du codage automatique à la perception consciente du temps dans le système nerveux central: un déficit fondamental dans la schizophrénie?(2016), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Saclay (COmUE), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: 0301 basic medicine, Physiology, Computer science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Action Potentials, computer.software_genre, Mathematical and Statistical Techniques, 0302 clinical medicine, Goodness of fit, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Medicine and Health Sciences, Feature (machine learning), Bandwidth (Signal Processing), lcsh:QH301-705.5, MESH: Action Potentials, Parametric statistics, Neurons, Mammals, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], Ecology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Physics, Brain, Eukaryota, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Signal Filtering, Electrophysiology, Computational Theory and Mathematics, Autoregressive model, Modeling and Simulation, Vertebrates, Physical Sciences, Parametric model, symbols, Engineering and Technology, Algorithm, Research Article, Models, Neurological, Neurophysiology, Research and Analysis Methods, Machine learning, Rodents, 03 medical and health sciences, Cellular and Molecular Neuroscience, symbols.namesake, MESH: Brain, MESH: Models, Neurological, Acoustic Signals, Sine Waves, Genetics, Animals, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, business.industry, Model selection, [SCCO.NEUR]Cognitive science/Neuroscience, Organisms, Probabilistic logic, Biology and Life Sciences, Acoustics, Filter (signal processing), Bandpass Filters, Nonlinear system, 030104 developmental biology, lcsh:Biology (General), Speech Signal Processing, Signal Processing, Amniotes, Artificial intelligence, Hilbert transform, business, Mathematical Functions, computer, 030217 neurology & neurosurgery, Neuroscience
Abstract: We address the issue of reliably detecting and quantifying cross-frequency coupling (CFC) in neural time series. Based on non-linear auto-regressive models, the proposed method provides a generative and parametric model of the time-varying spectral content of the signals. As this method models the entire spectrum simultaneously, it avoids the pitfalls related to incorrect filtering or the use of the Hilbert transform on wide-band signals. As the model is probabilistic, it also provides a score of the model “goodness of fit” via the likelihood, enabling easy and legitimate model selection and parameter comparison; this data-driven feature is unique to our model-based approach. Using three datasets obtained with invasive neurophysiological recordings in humans and rodents, we demonstrate that these models are able to replicate previous results obtained with other metrics, but also reveal new insights such as the influence of the amplitude of the slow oscillation. Using simulations, we demonstrate that our parametric method can reveal neural couplings with shorter signals than non-parametric methods. We also show how the likelihood can be used to find optimal filtering parameters, suggesting new properties on the spectrum of the driving signal, but also to estimate the optimal delay between the coupled signals, enabling a directionality estimation in the coupling., Author summary Neural oscillations synchronize information across brain areas at various anatomical and temporal scales. Of particular relevance, slow fluctuations of brain activity have been shown to affect high frequency neural activity, by regulating the excitability level of neural populations. Such cross-frequency-coupling can take several forms. In the most frequently observed type, the power of high frequency activity is time-locked to a specific phase of slow frequency oscillations, yielding phase-amplitude-coupling (PAC). Even when readily observed in neural recordings, such non-linear coupling is particularly challenging to formally characterize. Typically, neuroscientists use band-pass filtering and Hilbert transforms with ad-hoc correlations. Here, we explicitly address current limitations and propose an alternative probabilistic signal modeling approach, for which statistical inference is fast and well-posed. To statistically model PAC, we propose to use non-linear auto-regressive models which estimate the spectral modulation of a signal conditionally to a driving signal. This conditional spectral analysis enables easy model selection and clear hypothesis-testing by using the likelihood of a given model. We demonstrate the advantage of the model-based approach on three datasets acquired in rats and in humans. We further provide novel neuroscientific insights on previously reported PAC phenomena, capturing two mechanisms in PAC: influence of amplitude and directionality estimation.
Published: 2017
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35. Descending Command Neurons in the Brainstem that Halt Locomotion

Author: Kira Balueva, Carmelo Bellardita, Roberto Leiras, Ole Kiehn, Julien Bouvier, Andrea Fuchs, Vanessa Caldeira, Vittorio Caggiano, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), The Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet [Stockholm], and Institute of Physiology, Christian Albrechts University of Kiel
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Locomotion, MESH: Neurons, MESH: Central Pattern Generators, Stop signal, Biology, Reticular formation, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Spinal Cord, Mice, Glutamatergic, Neural Pathways, medicine, Animals, MESH: Animals, MESH: Mice, Medulla, Neurons, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Biochemistry, Genetics and Molecular Biology(all), MESH: Neural Pathways, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Anatomy, Spinal cord, Luminescent Proteins, medicine.anatomical_structure, Spinal Cord, nervous system, Developmental genetics, MESH: Brain Stem, Central Pattern Generators, Excitatory postsynaptic potential, MESH: Luminescent Proteins, Brainstem, Neuroscience, Locomotion, Brain Stem
Abstract: International audience; The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.
Published: 2015
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36. Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis

Author: Ekaterina Rogaeva, Julia Keith, Janice Robertson, Heather D. Durham, Benoit J. Gentil, Christine Marques, Beibei Zhao, Caroline Rouaux, Lorne Zinman, Sandra Minotti, Michael Tibshirani, McGill University = Université McGill [Montréal, Canada], University of Toronto, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Dieterle, Stéphane
Subjects: 0301 basic medicine, Cytoplasm, [SDV]Life Sciences [q-bio], Mutant, MESH: Neurons, MESH: DNA Helicases, medicine.disease_cause, MESH: Spinal Cord, Mice, 0302 clinical medicine, MESH: Animals, Amyotrophic lateral sclerosis, Genetics (clinical), MESH: Amyotrophic Lateral Sclerosis, Motor Neurons, Neurons, Mutation, MESH: RNA-Binding Protein FUS, Nuclear Proteins, Cell Differentiation, General Medicine, MESH: Transcription Factors, MESH: Protein Subunits, Cell biology, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Spinal Cord, MESH: Motor Neurons, MESH: Cell Differentiation, MESH: Mutation, Protein subunit, Biology, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Molecular Biology, MESH: Mice, Messenger RNA, MESH: Humans, MESH: Cytoplasm, Amyotrophic Lateral Sclerosis, DNA Helicases, MESH: Chromatin Assembly and Disassembly, Motor neuron, Chromatin Assembly and Disassembly, Spinal cord, medicine.disease, Protein Subunits, 030104 developmental biology, RNA-Binding Protein FUS, MESH: Nuclear Proteins, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.
Published: 2017
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37. Roles of Retinoic Acid Signaling in Shaping the Neuronal Architecture of the Developing Amphioxus Nervous System

Author: Jenifer C. Croce, Greta Garbarino, Elisabeth Zieger, Simona Candiani, Michael Schubert, Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Nervous system, MESH: Signal Transduction, MESH: Swimming, Neuronal specification and differentiation, Retinoic acid, MESH: Neurons, MESH: gamma-Aminobutyric Acid, Nervous System, chemistry.chemical_compound, Cephalochordate, Hox genes, MESH: Gene Expression Regulation, Developmental, retinoic acid, MESH: Animals, Hox gene, Dopamine (DA), MESH: Tyrosine 3-Monooxygenase, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, gamma-Aminobutyric Acid, MESH: Lancelets, Lancelets, Neurons, neurobiology, Neurogenesis, Genes, Homeobox, Gene Expression Regulation, Developmental, medicine.anatomical_structure, Neurology, Larva, Locomotory control, medicine.drug, Morphogen, Signal Transduction, animal structures, Tyrosine 3-Monooxygenase, retinoic acid, development, neurobiology, chordate evolution, chordate evolution, Neuroscience (miscellaneous), Hindbrain, Tretinoin, Biology, Models, Biological, gamma-Aminobutyric acid, γ-Aminobutyric acid (GABA), 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, development, Swimming, MESH: Nervous System, MESH: Tretinoin, Serotonin (5-HT), MESH: Genes, Homeobox, Neural tube, MESH: Models, Biological, Neurotransmitter systems, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Neuroscience, MESH: Larva
Abstract: International audience; The morphogen retinoic acid (RA) patterns vertebrate nervous systems and drives neurogenesis, but how these functions evolved remains elusive. Here, we show that RA signaling plays stage- and tissue-specific roles during the formation of neural cell populations with serotonin, dopamine, and GABA neurotransmitter phenotypes in amphioxus, a proxy for the ancestral chordate. Our data suggest that RA signaling restricts the specification of dopamine-containing cells in the ectoderm and of GABA neurons in the neural tube, probably by regulating Hox1 and Hox3 gene expression, respectively. The two Hox genes thus appear to serve distinct functions rather than to participate in a combinatorial Hox code. We were further able to correlate the RA signaling-dependent mispatterning of hindbrain GABA neurons with concomitant motor impairments. Taken together, these data provide new insights into how RA signaling and Hox genes contribute to nervous system as well as to motor control development in amphioxus and hence shed light on the evolution of these functions within vertebrates.
Published: 2017
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38. Refractoriness Accounts for Variable Spike Burst Responses in Somatosensory Cortex

Author: Alain Destexhe, Richard Kempter, Gabriel Curio, Bartosz Telenczuk, Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institute für Theoretische Biologie, and Department of Neurology, Universitätsmedizin Charité
Subjects: Refractory period, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, MESH: Wrist, Action Potentials, Electroencephalography, Somatosensory system, MESH: Signal Processing, Computer-Assisted, Macaque, MESH: Synapses, Spike burst, 0302 clinical medicine, MESH: Animals, EEG, MESH: Action Potentials, Neurons, 0303 health sciences, education.field_of_study, medicine.diagnostic_test, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Electric Stimulation, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Signal Processing, Computer-Assisted, Wrist, New Research, Response Variability, Touch Perception, Sensory and Motor Systems, Spike (software development), Female, MESH: Electrocorticography, burst, spike patterns, Population, Models, Neurological, Biology, MESH: Somatosensory Cortex, MESH: Macaca mulatta, modelling, 03 medical and health sciences, MESH: Models, Neurological, biology.animal, medicine, Animals, education, 030304 developmental biology, Models, Statistical, Somatosensory Cortex, Macaca mulatta, Electric Stimulation, Synapses, 8.1, Electrocorticography, Neuroscience, MESH: Female, 030217 neurology & neurosurgery, MESH: Models, Statistical, MESH: Touch Perception
Abstract: Neurons in the primary somatosensory cortex (S1) respond to peripheral stimulation with synchronised bursts of spikes, which lock to the macroscopic 600 Hz EEG waves. The mechanism of burst generation and synchronisation in S1 is not yet understood. Using models of single-neuron responses fitted to unit recordings from macaque monkeys, we show that these synchronised bursts are the consequence of correlated synaptic inputs combined with a refractory mechanism. In the presence of noise these models reproduce also the observed trial-to-trial response variability, where individual bursts represent one of many stereotypical temporal spike patterns. When additional slower and global excitability fluctuations are introduced the single-neuron spike patterns are correlated with the population activity, as demonstrated in experimental data. The underlying biophysical mechanism of S1 responses involves thalamic inputs arriving through depressing synapses to cortical neurons in a high-conductance state. Our findings show that a simple feedforward processing of peripheral inputs could give rise to neuronal responses with non-trivial temporal and population statistics. We conclude that neural systems could use refractoriness to encode variable cortical states into stereotypical short-term spike patterns amenable to processing at neuronal time scales (tens of milliseconds).Significance statementNeurons in the hand area of the primary somatosensory cortex respond to repeated presentation of the same stimulus with variable sequences of spikes, which can be grouped into distinct temporal spike patterns. In a simplified model, we show that such spike patterns are product of synaptic inputs and intrinsic neural properties. This model can reproduce both single-neuron and population responses only when a private variability in each neuron is combined with a multiplicative gain shared over whole population, which fluctuates over trials and might represent the dynamical state of the early stages of sensory processing. This phenomenon exemplifies a general mechanism of transforming the ensemble cortical states into precise temporal spike patterns at the level of single neurons.
Published: 2017
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39. Odor identity coding by distributed ensembles of neurons in the mouse olfactory cortex

Author: Brice Bathellier, Thomas Deneux, Alexander Fleischmann, Benjamin Roland, Kevin M. Franks, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Duke University Medical Center, Department of Neurobiology, Howard Hughes Medical Institute (HHMI), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and PERIGNON, Alain
Subjects: 0301 basic medicine, Olfactory system, MESH: Olfactory Perception, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Neurons, Piriform Cortex, neuroscience, Mice, 0302 clinical medicine, Cortex (anatomy), Piriform cortex, MESH: Animals, Biology (General), Neurons, education.field_of_study, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, General Neuroscience, musculoskeletal, neural, and ocular physiology, Optical Imaging, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, General Medicine, Anatomy, odor coding, medicine.anatomical_structure, cortex, Medicine, psychological phenomena and processes, Research Article, olfaction, QH301-705.5, Science, Models, Neurological, Population, Olfaction, Biology, MESH: Calcium Signaling, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Models, Neurological, medicine, Animals, Calcium Signaling, Olfactory memory, education, MESH: Mice, mouse, MESH: Odorants, MESH: Optical Imaging, General Immunology and Microbiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Olfactory Perception, Olfactory bulb, MESH: Piriform Cortex, 030104 developmental biology, Odor, nervous system, Odorants, Neuroscience, 030217 neurology & neurosurgery, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Abstract: Olfactory perception and behaviors critically depend on the ability to identify an odor across a wide range of concentrations. Here, we use calcium imaging to determine how odor identity is encoded in olfactory cortex. We find that, despite considerable trial-to-trial variability, odor identity can accurately be decoded from ensembles of co-active neurons that are distributed across piriform cortex without any apparent spatial organization. However, piriform response patterns change substantially over a 100-fold change in odor concentration, apparently degrading the population representation of odor identity. We show that this problem can be resolved by decoding odor identity from a subpopulation of concentration-invariant piriform neurons. These concentration-invariant neurons are overrepresented in piriform cortex but not in olfactory bulb mitral and tufted cells. We therefore propose that distinct perceptual features of odors are encoded in independent subnetworks of neurons in the olfactory cortex. DOI: http://dx.doi.org/10.7554/eLife.26337.001
Published: 2017
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40. Neuronal expression of a thyroid hormone receptor α mutation alters mouse behaviour

Author: O. Dkhissi-Benyahya, Sabine Richard, Frédéric Flamant, Nadine Aguilera, Marc Thevenet, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), BioSciences Lyon-Gerland (BLG), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon), Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Dominant negative, MESH: Neurons, Anxiety, medicine.disease_cause, MESH: Hypothyroidism, Behavioral Neuroscience, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Neurons, Mutation, Behavior, Animal, Depression, Thyroid, Brain, MESH: Stress, Psychological, Housing, Animal, MESH: Motor Activity, Circadian Rhythm, medicine.anatomical_structure, Conditional gene targeting, Female, medicine.symptom, Psychology, Thyroid Hormone Receptors alpha, medicine.medical_specialty, Thyroid Hormones, MESH: Mutation, MESH: Depression, MESH: Mice, Transgenic, MESH: Thyroid Hormone Receptors alpha, Mice, Transgenic, Motor Activity, 03 medical and health sciences, MESH: Brain, Animal model, Hypothyroidism, MESH: Thyroid Hormones, Internal medicine, medicine, Animals, [INFO]Computer Science [cs], MESH: Circadian Rhythm, Thyroid hormone receptor, MESH: Anxiety, MESH: Housing, Animal, MESH: Male, 030104 developmental biology, Endocrinology, Mood, MESH: Female, 030217 neurology & neurosurgery, Stress, Psychological, Hormone
Abstract: International audience; In humans, alterations in thyroid hormone signalling are associated with mood and anxiety disorders, but the neural mechanisms underlying such association are poorly understood. The present study investigates the involvement of neuronal thyroid hormone receptor α (TRα) in anxiety, using mouse genetics and Cre/loxP technology to specifically alter TRα signalling in neurons. We evaluated the behaviour of mice expressing a dominant negative, neuron-specific mutation of TRα (TRαAMI/Cre3 mice), using the elevated-plus maze, light-dark box and open-field tests. In a first experiment, mice were housed individually, and the behaviour of TRαAMI/Cre3 mice differed significantly from that of control littermates in these 3 tests, suggesting heightened anxiety. In a second experiment, designed to evaluate the robustness of the results with the same 3 tests, mice were housed in groups. In these conditions, the behaviour of TRαAMI/Cre3 mice differed from that of control littermates only in the light-dark box. Thus, TRαAMI/Cre3 mice appear to be more likely to develop anxiety under stressful housing conditions than control mice. These results suggest that in adult mice, thyroid hormone signalling in neurons, via TRα, is involved in the control of anxiety behaviour.
Published: 2017
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41. ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues

Author: Anke Witting, Eva Buck, Tanja Lucas, Jasmin Sprissler, Karin M Danzer, Karlheinz Holzmann, Kerstin Lang, Lara Barteczko, Tobias M. Boeckers, Patrick Weydt, Maria Demestre, Luc Dupuis, Hanna Bayer, Katrin S. Lindenberg, Noemi Pasquarelli, Julia Higelin, Albert C. Ludolph, University of Ulm (UUlm), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bonn, and Dieterle, Stéphane
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], MESH: Neurons, PGC-1α, MESH: Protein Isoforms, [SCCO]Cognitive science, Superoxide Dismutase-1, 0302 clinical medicine, Adipose Tissue, Brown, Neurotrophic factors, Protein Isoforms, MESH: Animals, Amyotrophic lateral sclerosis, Induced pluripotent stem cell, MESH: Amyotrophic Lateral Sclerosis, MESH: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, MESH: Superoxide Dismutase-1, Neurons, MESH: Muscle, Skeletal, MESH: RNA-Binding Protein FUS, Neurodegeneration, Brain, SOD1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, [SDV] Life Sciences [q-bio], Neurology, PPARGC1A, MESH: Mutation, MESH: Rats, MESH: Mice, Transgenic, Induced Pluripotent Stem Cells, Mice, Transgenic, MESH: Zebrafish Proteins, Biology, MESH: Induced Pluripotent Stem Cells, Neuroprotection, MESH: Adipose Tissue, Brown, Cell Line, lcsh:RC321-571, 03 medical and health sciences, MESH: Brain, Lou Gehrig disease, MESH: Mice, Inbred C57BL, Coactivator, medicine, Animals, Humans, RNA, Messenger, Muscle, Skeletal, MESH: Zebrafish, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, FUS, MESH: RNA, Messenger, MESH: Humans, [SCCO] Cognitive science, medicine.disease, Rats, MESH: Cell Line, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Mutation, Cancer research, RNA-Binding Protein FUS, Lactate, MESH: Disease Models, Animal, 030217 neurology & neurosurgery
Abstract: International audience; Background: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α).Methods: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations.Results: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations.Conclusion: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.
Published: 2017
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42. An Amplitude Modulation/Demodulation Scheme for Whisker-Based Texture Perception

Author: Georges Debrégeas, Daniel E. Shulz, Yves Boubenec, Laure Nayelie Claverie, Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Laboratoire Jean PERRIN, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, animal structures, Materials science, MESH: Rats, MESH: Biomechanical Phenomena, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Action Potentials, Sensory system, Texture (music), Somatosensory system, Vibration, Signal, MESH: Somatosensory Cortex, Amplitude modulation, MESH: Afferent Pathways, Discrimination, Psychological, Animals, Demodulation, MESH: Animals, MESH: Discrimination (Psychology), Rats, Wistar, MESH: Action Potentials, Neurons, Afferent Pathways, MESH: Vibration, Communication, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Tactile discrimination, business.industry, General Neuroscience, Whisking in animals, MESH: Vibrissae, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Somatosensory Cortex, Articles, MESH: Rats, Wistar, MESH: Touch, MESH: Male, Biomechanical Phenomena, Rats, Touch Perception, Touch, Vibrissae, Biological system, business, MESH: Touch Perception
Abstract: International audience; Whisking rodents can discriminate finely textured objects using their vibrissae. The biomechanical and neural processes underlying such sensory tasks remain elusive. Here we combine the use of model micropatterned substrates and high-resolution videography of rats' whiskers during tactile exploration to study how texture information is mechanically encoded in the whisker motion. A biomechanical modeling of the whisker is developed, which yields quantitative predictions of the spectral and temporal characteristics of the observed whisker kinetics, for any given topography. These texture-induced whisker vibrations are then replayed via a multiwhisker stimulator while recording neuronal responses in the barrel field of the primary somatosensory cortex (S1bf). These results provide a comprehensive description of the transduction process at play during fine texture sensing in rats. They suggest that the sensory system operates through a vibratory amplitude modulation/demodulation scheme. Fine textural properties are encoded in the time-varying envelope of the whisker-resonant vibrations. This quantity is then recovered by neural demodulation, as it effectively drives the spiking-rate signal of a large fraction of S1 cortical neurons. This encoding/decoding scheme is shown to be robust against variations in exploratory conditions, such as the scanning speed or pad-to-substrate distance, thus allowing for reliable tactile discrimination in realistic conditions.
Published: 2014
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43. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice

Author: Wolfgang H. Oertel, Bertrand Friguet, Gesine Respondek, Günter U. Höglinger, Matthias Höllerhage, Agathe Tarze, Stefanie Müssner, Mohamed Salama, Christel Depienne, Agnès Rastetter, Anderson de Andrade, Pierre Champy, Elizabeth Sumi Yamada, Guellaen, Georges, Experimental Neurology, Philipps University, Experimental Neuropathology Laboratory, University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Neurology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Cellulaire du vieillissement, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR83, Laboratoire de Pharmacognosie (BioCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Deutsche Forschungsgemeinschaft (HO2402/6-1, HO2402/8-1), the German Ministry of Education and Research (BMBF EF 10-54), the Centre National de la Recherche Scientifique (CNRS), a Marie Curie Incoming International Fellowship (21996 to E.S.Y.) and the German Academic Exchange Service (DAAD to A.C.F.d.A.)., University Hospital João de Barros Barreto-Federal University of Para - Universidade Federal do Para [Belem - Brésil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Intégrative (IFR-BI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Neurons, pharmacology [Enzyme Inhibitors], drug effects [Gene Expression Regulation], genetics [Gene Expression Regulation], drug effects [Microglia], MESH: Dose-Response Relationship, Drug, Mice, Lactones, chemistry.chemical_compound, 0302 clinical medicine, MESH: Animals, Phosphorylation, pharmacology [Furans], Enzyme Inhibitors, genetics [Arginine], Neurons, 0303 health sciences, Kinase, Neurodegeneration, neurodegeneration, MESH: Arginine, Tryptophan, Brain, MESH: Gene Expression Regulation, Mitochondria, MESH: tau Proteins, Cell biology, MESH: Microglia, Neurology, Biochemistry, MESH: Enzyme Inhibitors, drug effects [Brain], Microglia, genetics [Tryptophan], Tauopathy, Microtubule-Associated Proteins, MESH: Lactones, Genetically modified mouse, MESH: Mutation, MESH: Mice, Transgenic, MESH: Mitochondria, Annonacin, Mice, Transgenic, genetics [Mutation], MAPT protein, human, tau Proteins, Biology, Arginine, MESH: Brain, 03 medical and health sciences, drug effects [Phosphorylation], Developmental Neuroscience, MESH: Mice, Inbred C57BL, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, drug effects [Neurons], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ddc:610, Mortality, genetics [Phosphorylation], Furans, MESH: Mice, MESH: Tryptophan, 030304 developmental biology, MESH: Humans, MESH: Mortality, MESH: Phosphorylation, Dose-Response Relationship, Drug, Cyclin-dependent kinase 5, tauopathy, MESH: Furans, metabolism [Microtubule-Associated Proteins], annonacin, metabolism [Mitochondria], medicine.disease, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, genetics [tau Proteins], Somatodendritic compartment, Gene Expression Regulation, chemistry, environmental neurotoxin, metabolism [Brain], Mutation, pharmacology [Lactones], genetics [Mitochondria], microtubule-associated protein tau, 030217 neurology & neurosurgery
Abstract: International audience; Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.
Published: 2014
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44. Curcumin protects neuronal-like cells against acrolein by restoring Akt and redox signaling pathways

Author: Charles Ramassamy, Ghislain Djiokeng Paka, Rongbiao Pi, Sihem Doggui, Morgane Perrotte, Abdenour Belkacemi, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Department of Medical Biology, Faculty of Medicine, Université Laval [Québec] (ULaval), and Financial support was obtained from NSERC (CR). S.D. gratefully acknowledges financial support from the Foundation Armand-Frappier and GPD from AUF.
Subjects: MESH: Oxidation-Reduction, MESH: Signal Transduction, Antioxidant, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Neurons, MESH: NF-kappa B, Pharmacology, Antioxidants, Neuroblastoma, MESH: Reactive Nitrogen Species, chemistry.chemical_compound, Sirtuin 1, MESH: Curcumin, Acrolein, MESH: Sirtuin 1, Neurons, MESH: Glutathione, chemistry.chemical_classification, MESH: NF-E2-Related Factor 2, NF-kappa B, MESH: Reactive Oxygen Species, MESH: Neuroprotective Agents, Glutathione, Reactive Nitrogen Species, Neuroprotective Agents, Biochemistry, Oxidation-Reduction, Signal Transduction, Biotechnology, Curcumin, MESH: Cell Line, Tumor, NF-E2-Related Factor 2, Glutamate-Cysteine Ligase, Neuroprotection, Cell Line, Tumor, medicine, Humans, Protein kinase B, Reactive nitrogen species, Reactive oxygen species, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, MESH: Antioxidants, MESH: Neuroblastoma, MESH: Glutamate-Cysteine Ligase, chemistry, Nanoparticles, MESH: Acrolein, Reactive Oxygen Species, Proto-Oncogene Proteins c-akt, MESH: Nanoparticles, Food Science
Abstract: Scope The aim of the present study was to examine the neuroprotective effect of curcumin against the toxicity induced by acrolein and to identify its cellular mechanisms and targets. Methods and results Human neuroblastoma cells SK-N-SH were treated with acrolein. Curcumin, from 5 μM, was able to protect SK-N-SH cells against acrolein toxicity. The addition of curcumin restored the expression of γ-glutamylcysteine synthetase, reactive oxygen species, and reactive nitrogen species levels but had no effect on the decrease of glutathione (GSH) and on the elevation of protein carbonyls. Acrolein induced the activity of Nrf2, NF-κB, and Sirt1. These activations were prevented by the presence of curcumin. Acrolein also induced a decrease of the pAkt, which was counteracted by curcumin. To increase its solubility, we have encapsulated curcumin in a biodegradable poly(lactide-co-glycolide) based nanoparticulate formulation (Nps-Cur). Our results showed that 0.5 μM of Nps-Cur can protect neuronal cells challenged with acrolein while free curcumin was not able to display neuroprotection. Conclusion Our results provided evidence that curcumin was able to protect SK-N-SH cells against acrolein toxicity. This protection is mediated through the antioxidant, the redox, and the survival regulated pathways by curcumin. Moreover, our results demonstrated that Nps-Cur had higher capacity than curcumin to protect SK-N-SH cells against acrolein.
Published: 2013
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45. Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues

Author: Sophie Chauvet, Katja Burk, Fanny Mann, Institut de Biologie du Développement de Marseille (IBDM), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Vascular Endothelial Growth Factor A, MESH: Signal Transduction, MESH: Axons, MESH: Lymphatic Vessels, Angiogenesis, MESH: Receptors, Eph Family, VEGF receptors, Cellular differentiation, MESH: Neurons, Receptors, Cell Surface, MESH: Semaphorins, Semaphorins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Animals, Humans, MESH: Animals, Neuropilins, Growth cone, Molecular Biology, Neural cell, Lymphatic Vessels, Receptors, Eph Family, MESH: Receptors, Cell Surface, 030304 developmental biology, Neurons, Pharmacology, 0303 health sciences, MESH: Humans, MESH: Vascular Endothelial Growth Factor Receptor-2, MESH: Vascular Endothelial Growth Factor A, MESH: Blood Vessels, Cell Biology, Anatomy, Vascular Endothelial Growth Factor Receptor-2, Axons, Lymphatic system, biology.protein, Blood Vessels, Molecular Medicine, Axon guidance, MESH: Neuropilins, Signal transduction, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; Many organs, such as lungs, nerves, blood and lymphatic vessels, consist of complex networks that carry flows of information, gases, and nutrients within the body. The morphogenetic patterning that generates these organs involves the coordinated action of developmental signaling cues that guide migration of specialized cells. Precision guidance of endothelial tip cells by vascular endothelial growth factors (VEGFs) is well established, and several families of neural guidance molecules have been identified to exert guidance function in both the nervous and the vascular systems. This review discusses recent advances in VEGF research, focusing on the emerging role of neural guidance molecules as key regulators of VEGF function during vascular development and on the novel role of VEGFs in neural cell migration and nerve wiring.
Published: 2013
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46. Endogenous morphine and its metabolites in mammals: History, synthesis, localization and perspectives

Author: Yannick Goumon, Julie Vérièpe, Alexis Laux-Biehlmann, Jinane Mouheiche, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Goumon, Yannick
Subjects: medicine.drug_class, Dopamine, Analgesic, MESH: Neurons, Endogeny, Inflammation, MESH: Dopamine, Pharmacology, MESH: Mammals, [SCCO]Cognitive science, MESH: Opioid Peptides, Opioid receptor, medicine, Animals, MESH: Animals, Mammals, Neurons, Morphine Derivatives, Morphine, Chemistry, General Neuroscience, [SCCO] Cognitive science, History, 20th Century, MESH: Astrocytes, MESH: Morphine, Opioid Peptides, Astrocytes, MESH: Morphine Derivatives, TLR4, MESH: History, 20th Century, μ-opioid receptor, medicine.symptom, medicine.drug
Abstract: International audience; Morphine derived from Papaver somniferum is commonly used as an analgesic compound for pain relief. It is now accepted that endogenous morphine, structurally identical to vegetal morphine-alkaloid, is synthesized by mammalian cells from dopamine. Morphine binds mu opioid receptor and induces antinociceptive effects. However, the exact role of these compounds is a matter of debate although different links with infection, sepsis, inflammation, as well as major neurological pathologies (Parkinson's disease, schizophrenia) have been proposed. The present review describes endogenous morphine and morphine derivative discovery, synthesis, localization and potential implications in physiological and pathological processes.
Published: 2013
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47. The octadecaneuropeptide ODN prevents 6-hydroxydopamine-induced apoptosis of cerebellar granule neurons through a PKC-MAPK-dependent pathway

Author: Laurence Desrues, Hubert Vaudry, Jérôme Leprince, Mohamed Amri, David Vaudry, Olfa Masmoudi-Kouki, Hadhemi Kaddour, Yosra Hamdi, Hélène Castel, Marie-Christine Tonon, M. Basille, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biological Sciences, Université de Tunis El Manar (UTM)-Laboratory of Functional Neurophysiology and Pathology, Research Unit UR/11ES09, Faculty of Science of Tunis-Faculty of Science of Tunis, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Télécom SudParis (TSP), and Université de Tunis El Manar (UTM)
Subjects: MAPK/ERK pathway, MESH: Cyclin D1, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, medicine.disease_cause, Biochemistry, 0302 clinical medicine, Cerebellum, MESH: Caspase 3, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cyclin D1, MESH: Animals, Phosphorylation, MESH: Peptide Fragments, Protein Kinase C, Diazepam Binding Inhibitor, Neurons, MESH: Glutathione, 0303 health sciences, MESH: Oxidative Stress, Caspase 3, Chemistry, MESH: Reactive Oxygen Species, hemic and immune systems, MESH: Neuroprotective Agents, respiratory system, Glutathione, 3. Good health, Cell biology, Neuroprotective Agents, Programmed cell death, MESH: Rats, MAP Kinase Signaling System, Neuroprotection, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, Rats, Wistar, Oxidopamine, Protein kinase C, 030304 developmental biology, Hydroxydopamine, MESH: Phosphorylation, MESH: MAP Kinase Signaling System, MESH: Apoptosis, Neuropeptides, MESH: Sympatholytics, MESH: Rats, Wistar, MESH: Protein Kinase C, Peptide Fragments, MESH: Cerebellum, Rats, MESH: Oxidopamine, Oxidative Stress, Metabotropic receptor, nervous system, Sympatholytics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, Reactive Oxygen Species, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Oxidative stress, induced by various neurodegenerative diseases, initiates a cascade of events leading to apoptosis, and thus plays a critical role in neuronal injury. In this study, we have investigated the potential neuroprotective effect of the octadecaneuropeptide (ODN) on 6-hydroxydopamine (6-OHDA)-induced oxidative stress and apoptosis in cerebellar granule neurons (CGN). ODN, which is produced by astrocytes, is an endogenous ligand for both central-type benzodiazepine receptors (CBR) and a metabotropic receptor. Incubation of neurons with subnanomolar concentrations of ODN (10⁻¹⁸ to 10⁻¹² M) inhibited 6-OHDA-evoked cell death in a concentration-dependent manner. The effect of ODN on neuronal survival was abrogated by the metabotropic receptor antagonist, cyclo₁₋₈ [DLeu⁵]OP, but not by a CBR antagonist. ODN stimulated polyphosphoinositide turnover and ERK phosphorylation in CGN. The protective effect of ODN against 6-OHDA toxicity involved the phospholipase C/ERK MAPK transduction cascade. 6-OHDA treatment induced an accumulation of reactive oxygen species, an increase of the expression of the pro-apoptotic gene Bax, a drop of the mitochondrial membrane potential and a stimulation of caspase-3 activity. Exposure of 6-OHDA-treated cells to ODN blocked all the deleterious effects of the toxin. Taken together, these data demonstrate for the first time that ODN is a neuroprotective agent that prevents 6-OHDA-induced oxidative stress and apoptotic cell death.
Published: 2013
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48. Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin

Author: Luc Maroteaux, Silvina L. Diaz, Patricia Gaspar, Bruno Giros, Sebastian Jessberger, Sophie Scotto-Lomassese, Sara Trowbridge, Nicolas Narboux-Nême, Evan S. Deneris, Felix B. Kleine Borgmann, Maroteaux, Luc, Maladies Neurologiques et Psychiatriques - Genetic exploration of the diversity of central serotonin systems. - - Serodiversity2008 - ANR-08-MNPS-0032 - MNP - VALID, Serotonin and GABA-B receptors in anxiety : from developmental risk factors to treatment. - DEVANX - - EC:FP7:HEALTH2008-02-01 - 2012-07-31 - 201714 - VALID, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brain Research Institute, Universität Zürich [Zürich] = University of Zurich (UZH), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Psychiatrie, McGill University = Université McGill [Montréal, Canada]-Institut Universitaire en Santé Mentale Douglas, Neurosciences Department, Case Western Reserve University [Cleveland], This research was funded by Institut National de la Recherche et de la Santé (Inserm), the Université Pierre et Marie Curie (Paris 6), the European Commission (FP7-health-2007-A-201714) and the Agence Nationale pour la recherche (ANR-MNP-neur-032). SD and NN were supported by fellowships from the Région Ile de France, ST was supported by the Henry Russell Shaw travelling fellowship from Harvard University., ANR-08-MNPS-0032,Serodiversity,Genetic exploration of the diversity of central serotonin systems.(2008), European Project: 201714,EC:FP7:HEALTH,FP7-HEALTH-2007-A,DEVANX(2008), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), University of Zurich, and Gaspar, Patricia
Subjects: Male, hippocampus, MESH: Neurons, Hippocampus, MESH: Vesicular Monoamine Transport Proteins, Hippocampal formation, ADULT NEUROGENESIS, MESH: Mice, Knockout, Subgranular zone, MESH: Serotonin Antagonists, Mice, 0302 clinical medicine, GENETIC MOUSE MODELS, MESH: Animals, 5-hydroxytryptamine depletion, Mice, Knockout, Neurons, 0303 health sciences, General Neuroscience, Neurogenesis, Fenclonine, 2800 General Neuroscience, Bioquímica y Biología Molecular, adult neurogenesis, medicine.anatomical_structure, MESH: Cell Survival, para-chlorophenylalanine, Female, Serotonin Antagonists, CIENCIAS NATURALES Y EXACTAS, medicine.medical_specialty, Serotonin, MESH: Receptors, Serotonin, Cell Survival, 610 Medicine & health, Biology, Serotonergic, MESH: Fenclonine, Ciencias Biológicas, 03 medical and health sciences, genetic mouse models, MESH: Mice, Inbred C57BL, Internal medicine, Genetic model, 5-HYDROXYTRYPTAMINE DEPLETION, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, pattern separation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, 10242 Brain Research Institute, Dentate gyrus, MESH: Male, MESH: Neurogenesis, Mice, Inbred C57BL, Endocrinology, nervous system, Receptors, Serotonin, Vesicular Monoamine Transport Proteins, Dentate Gyrus, HIPPOCAMPUS, 570 Life sciences, biology, MESH: Serotonin, Neuroscience, MESH: Female, 030217 neurology & neurosurgery, MESH: Dentate Gyrus
Abstract: Increased adult neurogenesis is a major neurobiological correlate of the beneficial effects of antidepressants. Indeed, selective serotonin (5-HT) re-uptake inhibitors, which increase 5-HT transmission, enhance adult neurogenesis in the dentate gyrus (DG) of the hippocampus. However, the consequences of 5-HT depletion are still unclear as studies using neurotoxins that target serotonergic neurons reached contradictory conclusions on the role of 5-HT on DG cell proliferation. Here, we analysed two genetic models of 5-HT depletion, the Pet1-/- and the VMAT2f/f; SERTcre/+ mice, which have, respectively, 80 and 95% reductions in hippocampal 5-HT. In both models, we found unchanged cell proliferation of the neural precursors in the DG subgranular zone, whereas a significant increase in the survival of newborn neurons was noted 1 and 4 weeks after BrdU injections. This pro-survival trait was phenocopied pharmacologically with 5-HT synthesis inhibitor PCPA treatment in adults, indicating that this effect was not developmental. Furthermore, a 1-week administration of the 5-HT1A receptor agonist 8-OH-DPAT in Pet1-/- and PCPA-treated mice normalised hippocampal cell survival. Overall, our results indicate that constitutive 5-HT depletion does not alter the proliferation of neural precursors in the DG but promotes the survival of newborn cells, an effect which involves activation of postsynaptic 5-HT1A receptors. The role of 5-HT in selective neuronal elimination points to a new facet in its multiple effects in controlling neural circuit maturation. Fil: Diaz, Silvina Laura. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; Argentina Fil: Narboux Nême, Nicolas. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia Fil: Trowbridge, Sara. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia Fil: Scotto Lomassese, Sophie. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia Fil: Kleine Borgemann, Felix B.. Universitat Zurich; Suiza Fil: Jessberger, Sebastian. Universitat Zurich; Suiza Fil: Giros, Bruno. Universite Pierre Et Marie Curie; Francia. Centre National de la Recherche Scientifique; Francia. Mc Gill University; Canadá Fil: Maroteaux, Luc. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia Fil: Deneris, Evan. Case Western Reserve University; Estados Unidos Fil: Gaspar, Patricia. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia
Published: 2013
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49. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

Author: Aurélie Poulet, Alexandra Benchoua, Richard Delorme, Laure Chatrousse, Francis Cogé, Delphine Héron, Frédérique Rodet-Amsellem, Millan Mark, Claire Boissart, Thomas Bourgeron, Hélène Darville, Anselme L. Perrier, Caroline Nava, Julie Pernelle, Margot Jarrige, Marc Peschanski, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, French Biodiversity Agency, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Hydrosystèmes et Bioprocédés (UR HBAN), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Division of General Internal Medicine (DGIM), Université de Genève = University of Geneva (UNIGE), Institut de Recherche Servier, SERVIER, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study has been in part funded by grants from 'Investissements d'Avenir' – (ANR-11-INBS-0009 - INGESTEM – and ANR-11-INBS-0011 - NeurATRIS), the French National Research Agency ANR (ANR-13-SAMA-0006, SynDivAutism), the Laboratory of Excellence GENMED (ANR-10-LABX-0013), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, and the Fondamental Foundation. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository, as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are GM 1869., The authors are thankful to I-Stem's HTS platform staff for constant technical support. We thank the cell bank of Pitié-Salpétrière hospital and the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment, information, sampling and fibroblast preparation. H.D. received a PhD grant from Servier's Laboratories. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon)., ANR-11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), d'Eggis, Gilles, Infrastructures - INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES - - INGESTEM2011 - ANR-11-INBS-0009 - INBS - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], University of Geneva [Switzerland], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], ANR-11-INBS-0009/11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011/11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, GAS, Global Assessment Scale, 0301 basic medicine, VPA, valproic acid, Autism Spectrum Disorder, Cellular differentiation, Autism, Human Embryonic Stem Cells, Drug repurposing, MESH: Neurons, lcsh:Medicine, hESC, human embryonic stem cells, Haploinsufficiency, Severity of Illness Index, RPM, Raven's progressive matrices, MESH: Nerve Tissue Proteins, MESH: Neuronal Plasticity, Induced pluripotent stem cell, SHANK3, Cells, Cultured, ASD, autism spectrum disorders, Neurons, ADOS, Autism Diagnosis Observational Scale, Genetics, MESH: Autism Spectrum Disorder, lcsh:R5-920, Neuronal Plasticity, PPVT, Peabody Picture Vocabulary Test, PSC, pluripotent stem cells, Cell Differentiation, General Medicine, Neural stem cell, 3. Good health, Drug repositioning, Phenotype, Autism spectrum disorder, MESH: Pluripotent Stem Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, lcsh:Medicine (General), Research Paper, MESH: Cells, Cultured, Pluripotent Stem Cells, MESH: Cell Differentiation, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Nerve Tissue Proteins, ADHD, Attention Deficit Hyperactive Disorder, Lithium, SHANK3, SH3 and multiple ankyrin repeat domains 3, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, iPSC, induced pluripotent stem cells, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, High throughput screening, MESH: Severity of Illness Index, medicine, Humans, NSC, neural stem cells, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], HTS, high throughput screening, MESH: RNA, Messenger, Valproate, MESH: Humans, MESH: Lithium, business.industry, Valproic Acid, MESH: Transcriptome, lcsh:R, MESH: Human Embryonic Stem Cells, medicine.disease, FDA, Food and Drug Administration, Embryonic stem cell, MESH: Male, DMSO, dimethylsulfoxyde, PPIA, Peptidylprolyl Isomerase A, 030104 developmental biology, SRS, Social Responsiveness Scale, Transcriptome, business, Neuroscience, MESH: Valproic Acid
Abstract: Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments., Highlights • Human neurons were used to screen for compounds correcting symptoms associated with SHANK3 haploinsufficiency syndrome. • Screening criteria were the ability to increase SHANK3 expression and to increase glutamatergic transmission. • Selected hit compounds were then validated using neurons differentiated from individuals with SHANK3 disrupting mutations. • Lithium was selected and delivered to one of SHANK3 patient showing encouraging positive clinical outcomes after one year. The clinical heterogeneity between individuals affected by autism makes it difficult to anticipate the effectiveness of a treatment. Furthermore, clinical practice lacks biological tools to help make such decisions. Here we use neurons, produced from pluripotent stem cells derived from patients affected by SHANK3 haploinsufficiency syndrome, to test the efficiency of therapeutic compounds. We screened the biological activity of more than 200 compounds on SHANK3 expression. Lithium was ultimately selected and delivered to one patient with a SHANK3-disruptive mutation. This resulted in a positive outcome, as determined by improved autistic core symptoms, thus supporting the usefulness of this type of predictive approach.
Published: 2016
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50. Local field potentials primarily reflect inhibitory neuron activity in human and monkey cortex

Author: Sydney S. Cash, Michel Le Van Quyen, Alain Destexhe, Eric Halgren, Nima Dehghani, Bartosz Telenczuk, Nicholas G. Hatsopoulos, Unité de Neurosciences Information et Complexité [Gif sur Yvette] (UNIC), Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Wyss Institute for Biologically Inspired Engineering [Harvard University], Harvard University [Cambridge], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Massachusetts General Hospital [Boston], Multimodal Imaging Laboratory, Department Radiology and Neurosciences (UCSD), University of California [San Diego] (UC San Diego), University of California-University of California, University of Chicago, PERIGNON, Alain, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS), and University of California (UC)
Subjects: genetic structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Neurons, Local field potential, Hippocampal formation, 0302 clinical medicine, Cortex (anatomy), MESH: Animals, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Middle Aged, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Electroencephalography, MESH: Neural Inhibition, Middle Aged, medicine.anatomical_structure, MESH: Young Adult, Cerebral cortex, Neurological, Excitatory postsynaptic potential, Female, Adult, Biology, Inhibitory postsynaptic potential, Article, MESH: Macaca mulatta, Young Adult, 03 medical and health sciences, Spatio-Temporal Analysis, MESH: Spatio-Temporal Analysis, MESH: Electroencephalography, Inhibitory neuron, medicine, Animals, Humans, 030304 developmental biology, MESH: Humans, Neurosciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neural Inhibition, MESH: Adult, Macaca mulatta, MESH: Cerebral Cortex, nervous system, Neuron, MESH: Female, Neuroscience, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery
Abstract: The local field potential (LFP) is generated by large populations of neurons, but unitary contribution of spiking neurons to LFP is not well characterised. We investigated this contribution in multi-electrode array recordings from human and monkey neocortex by examining the spike-triggered LFP average (st-LFP). The resulting st-LFPs were dominated by broad spatio-temporal components due to ongoing activity, synaptic inputs and recurrent connectivity. To reduce the spatial reach of the st-LFP and observe the local field related to a single spike we applied a spatial filter, whose weights were adapted to the covariance of ongoing LFP. The filtered st-LFPs were limited to the perimeter of 800 μm around the neuron, and propagated at axonal speed, which is consistent with their unitary nature. In addition, we discriminated between putative inhibitory and excitatory neurons and found that the inhibitory st-LFP peaked at shorter latencies, consistently with previous findings in hippocampal slices. Thus, in human and monkey neocortex, the LFP reflects primarily inhibitory neuron activity.
Published: 2016
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