Descriptor: "[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology" - Searchworks@Jio Institute Digital Library Search Results

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6,737 results on '"[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology"'

1. Microtubule remodelling as a driving force of axon guidance and pruning

Author: Coralie Fassier, Xavier Nicol, Melody Atkins, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Nicol, Xavier
Subjects: Axon guidance, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, tubulin isotypes, tubulin posttranslational modifications, Cell Biology, Axon pruning, Microtubules, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Microtubule-associated proteins, Developmental Biology
Abstract: International audience; The establishment of neuronal connectivity relies on the microtubule (MT) cytoskeleton, which provides mechanical support, roads for axonal transport and mediates signalling events. Fine-tuned spatiotemporal regulation of MT functions by tubulin post-translational modifications and MT-associated proteins is critical for the coarse wiring and subsequent refinement of neuronal connectivity. The defective regulation of these processes causes a wide range of neurodevelopmental disorders associated with connectivity defects. This review focuses on recent studies unravelling how MT composition, post-translational modifications and associated proteins influence MT functions in axon guidance and/or pruning to build functional neuronal circuits. We here summarise experimental evidence supporting the key role of this network as a driving force for growth cone steering and branch-specific axon elimination. We further provide a global overview of the MT-interactors that tune developing axon behaviours, with a special emphasis on their emerging versatility in the regulation of MT dynamics/structure. Recent studies establishing the key and highly selective role of the tubulin code in the regulation of MT functions in axon pathfinding are also reported. Finally, our review highlights the emerging molecular links between these MT regulation processes and guidance signals that wire the nervous system.
Published: 2023

2. Controlled Tau Cleavage in Cells Reveals Abnormal Localizations of Tau Fragments

Author: Fourest-Lieuvin, Anne, Vinit, Angélique, Blot, Béatrice, Perrot, Anthime, Denarier, Eric, Saudou, Frédéric, Arnal, Isabelle, Fourest-Lieuvin, Anne, 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), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)
Subjects: Protein cleavage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Neuroscience, nucleus, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], TEV protease, Microtubule, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Tau, Actin
Abstract: International audience; In several forms of dementia, such as Alzheimer's disease, the cytoskeleton-associated protein tau undergoes proteolysis, giving rise to fragments that have a toxic impact on neuronal homeostasis. How these fragments interact with cellular structures, in particular with the cytoskeleton, is currently incompletely understood. Here, we developed a method, derived from a Tobacco Etch Virus (TEV) protease system, to induce controlled cleavage of tau at specific sites. Five tau proteins containing specific TEV recognition sites corresponding to pathological proteolytic sites were engineered, and tagged with GFP at one end and mCherry at the other. After a controlled cleavage to produce GFP-N-terminal and C-terminal-mCherry fragments, we followed the fate of tau fragments in cells. Our results showed that whole engineered tau proteins associate with the cytoskeleton similarly to the non-modified tau, whereas tau fragments adopted different localizations with respect to the actin and microtubule cytoskeletons. These distinct localizations were confirmed by expressing each separate fragment in cells. Some cleavages-in particular cleavages at amino-acid positions 124 or 256-displayed a certain level of cellular toxicity, with an unusual relocalization of the N-terminal fragments to the nucleus. Based on the data presented here, inducible cleavage of tau by the TEV protease appears to be a valuable tool to reproduce tau fragmentation in cells and study the resulting consequences on cell physiology.
Published: 2023

3. PROJECTION METHODS FOR NEURAL FIELD EQUATIONS

Author: Daniele Avitabile, Department of Mathematics [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Mathematics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Neuroscience - Systems & Network Neuroscience
Subjects: Numerical Analysis, Quantitative Biology::Neurons and Cognition, mathematical neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Applied Mathematics, Numerical Analysis (math.NA), Dynamical Systems (math.DS), integro-differential equations, Computational Mathematics, FOS: Mathematics, projection methods, Mathematics - Numerical Analysis, Mathematics - Dynamical Systems, [MATH.MATH-NA]Mathematics [math]/Numerical Analysis [math.NA]
Abstract: International audience; Neural field models are nonlinear integro-differential equations for the evolution of neuronal activity, and they are a prototypical large-scale, coarse-grained neuronal model in continuum cortices. Neural fields are often simulated heuristically and, in spite of their popularity in mathematical neuroscience, their numerical analysis is not yet fully established. We introduce generic projection methods for neural fields, and derive a-priori error bounds for these schemes. We extend an existing framework for stationary integral equations to the time-dependent case, which is relevant for neuroscience applications. We find that the convergence rate of a projection scheme for a neural field is determined to a great extent by the convergence rate of the projection operator. This abstract analysis, which unifies the treatment of collocation and Galerkin schemes, is carried out in operator form, without resorting to quadrature rules for the integral term, which are introduced only at a later stage, and whose choice is enslaved by the choice of the projector. Using an elementary timestepper as an example, we demonstrate that the error in a time stepper has two separate contributions: one from the projector, and one from the time discretisation. We give examples of concrete projection methods: two collocation schemes (piecewise-linear and spectral collocation) and two Galerkin schemes (finite elements and spectral Galerkin); for each of them we derive error bounds from the general theory, introduce several discrete variants, provide implementation details, and present reproducible convergence tests.
Published: 2023

4. Toxic CUG RNA repeats disrupt developmentally-regulated splicing in oligodendrocytes causing transient hypomyelination in a mouse model of myotonic dystrophy

Author: Lallemant, Louison, Braz, Sandra, González-Barriga, Anchel, Magneron, Paul, Cordier, Aurélien, Huguet-Lachon, Aline, Schmitt, Alain, Langui, Dominique, Auboeuf, Didier, Martinat, Cécile, Bourgeois, Cyril F, Gourdon, Geneviève, Gomes-Pereira, Mário, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), 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), 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)-Université Paris-Saclay-Généthon, AFM-Téléthon (19920), Fondation Bettencourt Schueller (France), Fondation pour la Recherche Médicale (France), Région Ile-de-France., and Network Glia e.V.
Subjects: transgenic mouse, myelin, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, RNA biology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myotonic dystrophy of type 1, oligodendrocytes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Trinucleotide Repeat Expansion
Abstract: International audience; Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder, characterised by cognitive and behavioural impairment, in addition to the typical muscle pathology. Imaging studies revealed widespread white matter lesions in DM1 patients, which may be partially explained by local demyelination. DM1 is caused by the abnormal expansion of non-coding CTG trinucleotide repeat, which is transcribed into toxic CUG RNA that accumulates in nuclear RNA foci and disrupts critical RNA-binding proteins. To investigate the impact of RNA toxicity on myelin biology, we used a transgenic mouse model of DM1, known as the DMSXL mice, which express expanded CUG transcripts in multiple tissues and cell types.We found delayed axon myelination of the corpus callosum at two weeks of age, which later recovered at four months. Early myelin defects were linked to an overall reduction in the number of oligodendroglia cells, specifically myelinating oligodendrocytes (OL), with a concurrent increase in oligodendrocyte progenitor cells (OPC). These phenotypes were accompanied by abundant RNA foci and splicing dysregulation in oligodendroglia, which were more pronounced at two weeks. Taking advantage of primary cell models, we investigated the mechanisms triggered by toxic CUG RNA in oligodendroglia. OPC isolated from DMSXL newborns exhibited impaired differentiation into fully ramified OLs in culture, a defect we confirmed in human oligodendroglia derived from DM1 patients. RNA sequencing revealed expression and splicing changes in DMSXL OL that affect transcripts related to the cytoskeleton and cell differentiation. Importantly, the transcriptomic defects of DMSXL OL recreated expression and splicing profiles typical of immature OPC.In conclusion, toxic CUG RNA disrupts the molecular program of oligodendroglia differentiation, impairing the transcriptome changes occurring during the OPC-OL transition and leading to transient hypomyelination in mice.
Published: 2023

5. Disease Progression Score Estimation From Multimodal Imaging and MicroRNA Data Using Supervised Variational Autoencoders

Author: Virgilio Kmetzsch, Emmanuelle Becker, Dario Saracino, Daisy Rinaldi, Agnes Camuzat, Isabelle Le Ber, Olivier Colliot, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), 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), Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), The research leading to these results has received funding from the French government under management of Agence Nationale de la Recherche, references ANR-19-P3IA-0001 (PRAIRIE 3IA Institute), ANR-10-IAIHU-06, project PREV-DEMALS (grant number ANR-14-CE15-0016-07), and from the Inria Project Lab Program (project Neuromarkers)., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-14-CE15-0016,PREV-DEMALS,Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA)(2014), Colliot, Olivier, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, and Appel à projets générique - Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) - - PREV-DEMALS2014 - ANR-14-CE15-0016 - Appel à projets générique - VALID
Subjects: [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Deep learning, MicroRNA, Neuroimaging, Health Informatics, Variational autoencoder, Neurodegenerative disease, Disease progression score, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Computer Science Applications, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Multimodal data, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Health Information Management, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Electrical and Electronic Engineering, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; Frontotemporal dementia and amyotrophic lateral sclerosis are rare neurodegenerative diseases with no effective treatment. The development of biomarkers allowing an accurate assessment of disease progression is crucial for evaluating new therapies. Concretely, neuroimaging and transcriptomic (microRNA) data have been shown useful in tracking their progression. However, no single biomarker can accurately measure progression in these complex diseases. Additionally, large samples are not available for such rare disorders. It is thus essential to develop methods that can model disease progression by combining multiple biomarkers from small samples. In this paper, we propose a new framework for computing a disease progression score (DPS) from cross-sectional multimodal data. Specifically, we introduce a supervised multimodal variational autoencoder that can infer a meaningful latent space, where latent representations are placed along a disease trajectory. A score is computed by orthogonal projections onto this path. We evaluate our framework with multiple synthetic datasets and with a real dataset containing 14 patients, 40 presymptomatic genetic mutation carriers and 37 controls from the PREV-DEMALS study. There is no ground truth for the DPS in real-world scenarios, therefore we use the area under the ROC curve (AUC) as a proxy metric. Results with the synthetic datasets support this choice, since the higher the AUC, the more accurate the predicted simulated DPS. Experiments with the real dataset demonstrate better performance in comparison with stateof-the-art approaches. The proposed framework thus leverages cross-sectional multimodal datasets with small sample sizes to objectively measure disease progression, with potential application in clinical trials.
Published: 2022

6. In vivo targeting and multimodal imaging of cerebral amyloid-β aggregates using hybrid GdF3 nanoparticles

Author: Frédéric Lerouge, Elodie Ong, Hugo Rositi, Francis Mpambani, Lise-Prune Berner, Radu Bolbos, Cécile Olivier, Françoise Peyrin, Vinu K Apputukan, Cyrille Monnereau, Chantal Andraud, Frederic Chaput, Yves Berthezène, Bettina Braun, Mathias Jucker, Andreas KO Åslund, Sofie Nyström, Per Hammarström, K Peter R Nilsson, Mikael Lindgren, Marlène Wiart, Fabien Chauveau, Stephane Parola, Laboratoire de Chimie - UMR5182 (LC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-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 d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-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 Grenoble Alpes (UGA), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Linköping University (LIU), Norwegian University of Science and Technology (NTNU), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), ANR-15-CE18-0026,NanoBrain,Imagerie de l'inflammation cérébrale dans l'AVC ischémique : développement d'une sonde nanoparticulaire multimodale & méthodes d'imagerie cérébrale(2015), and European Project: 242098,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,LUPAS(2009)
Subjects: [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biomedical Engineering, Medicine (miscellaneous), multimodal imaging, General Materials Science, Bioengineering, luminescent-conjugated polythiophenes, Development, gadolinium fluoride nanoparticles, amyloid-beta
Abstract: Aim: To propose a new multimodal imaging agent targeting amyloid-β (Aβ) plaques in Alzheimer’s disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer’s disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood–brain barrier status. Nevertheless, multimodal imaging showed successful Aβ targeting in both transgenic mice and Aβ fibril-injected rats.
Published: 2022

7. Microglia states and nomenclature

Author: Rosa C. Paolicelli, Amanda Sierra, Beth Stevens, Marie-Eve Tremblay, Adriano Aguzzi, Bahareh Ajami, Ido Amit, Etienne Audinat, Ingo Bechmann, Mariko Bennett, Frederick Bennett, Alain Bessis, Knut Biber, Staci Bilbo, Mathew Blurton-Jones, Erik Boddeke, Dora Brites, Bert Brône, Guy C. Brown, Oleg Butovsky, Monica J. Carson, Bernardo Castellano, Marco Colonna, Sally A. Cowley, Colm Cunningham, Dimitrios Davalos, Philip L. De Jager, Bart de Strooper, Adam Denes, Bart J.L. Eggen, Ukpong Eyo, Elena Galea, Sonia Garel, Florent Ginhoux, Christopher K. Glass, Ozgun Gokce, Diego Gomez-Nicola, Berta González, Siamon Gordon, Manuel B. Graeber, Andrew D. Greenhalgh, Pierre Gressens, Melanie Greter, David H. Gutmann, Christian Haass, Michael T. Heneka, Frank L. Heppner, Soyon Hong, David A. Hume, Steffen Jung, Helmut Kettenmann, Jonathan Kipnis, Ryuta Koyama, Greg Lemke, Marina Lynch, Ania Majewska, Marzia Malcangio, Tarja Malm, Renzo Mancuso, Takahiro Masuda, Michela Matteoli, Barry W. McColl, Veronique E. Miron, Anna Victoria Molofsky, Michelle Monje, Eva Mracsko, Agnes Nadjar, Jonas J. Neher, Urte Neniskyte, Harald Neumann, Mami Noda, Bo Peng, Francesca Peri, V. Hugh Perry, Phillip G. Popovich, Clare Pridans, Josef Priller, Marco Prinz, Davide Ragozzino, Richard M. Ransohoff, Michael W. Salter, Anne Schaefer, Dorothy P. Schafer, Michal Schwartz, Mikael Simons, Cody J. Smith, Wolfgang J. Streit, Tuan Leng Tay, Li-Huei Tsai, Alexei Verkhratsky, Rommy von Bernhardi, Hiroaki Wake, Valérie Wittamer, Susanne A. Wolf, Long-Jun Wu, Tony Wyss-Coray, Université de Lausanne = University of Lausanne (UNIL), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), McGill University = Université McGill [Montréal, Canada], University of Victoria [Canada] (UVIC), University of British Columbia [Vancouver], Universität Zürich [Zürich] = University of Zurich (UZH), Oregon Health and Science University [Portland] (OHSU), Weizmann Institute of Science [Rehovot, Israël], Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Children’s Hospital of Philadelphia (CHOP ), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), 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)-École normale supérieure - Paris (ENS-PSL), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AbbVie Deutschland GmbH & Co KG, Abbott GmbH & Co KG, Duke University [Durham], University of California [Irvine] (UC Irvine), University of California (UC), Universidade de Lisboa, This work was supported by grants from the Dementia Research Switzerland– Synapsis Foundation, Swiss National Science Foundation (SNSF 310030_197940), and European Research Council (ERC StGrant REMIND 804949) to R.C.P., the Spanish Ministry of Science and Innovation Competitiveness MCIN/AEI/ 10.13039/501100011033 and FEDER ‘‘A way to make Europe’’ (RTI2018099267-B-I00 and RYC-2013-12817), a Tatiana Foundation award (P-048FTPGB 2018), and a Basque Government Department of Education project (PIBA 2020_1_0030) to A.S., Cure Alzheimer’s Fund and Alzheimer’s Association to B.S., the Canadian Institutes of Health Research (foundation grant 341846, project grant 461831) and Natural Sciences and Engineering Research Council of Canada (discovery grant RGPIN-2014-05308) to M.E.T. M.E.T. is a Tier II Canada Research Chair in Neurobiology of Aging and Cognition. This work was also funded by DFG CRC/TRR167 ‘‘NeuroMac’’ to I.A., J.P., M.P., and S.J. and by DFG SFB 1052, Project 209933838 to I.B. Australian Research Council support for project DP150104472 to M.B.G. is gratefully acknowledged., European Project: DP150104472,ARC::Discovery Projects(2015), European Project: 7469381(1974), European Project: 7244968(1972), Brown, Guy [0000-0002-3610-1730], and Apollo - University of Cambridge Repository
Subjects: Neurology & Neurosurgery, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Neuroscience, Neurosciences, Psychology, Cognitive Sciences, ddc:610, Human medicine, Microglia
Abstract: International audience; Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.
Published: 2022

8. Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains ofKCNH5

Author: Hannah C. Happ, Lynette G. Sadleir, Matthew Zemel, Guillem de Valles-Ibáñez, Michael S. Hildebrand, Allyn McConkie-Rosell, Marie McDonald, Halie May, Tristan Sands, Vimla Aggarwal, Christopher Elder, Timothy Feyma, Allan Bayat, Rikke S. Møller, Christina D. Fenger, Jens Erik Klint Nielsen, Anita N. Datta, Kathleen M. Gorman, Mary D. King, Natalia D. Linhares, Barbara K. Burton, Andrea Paras, Sian Ellard, Julia Rankin, Anju Shukla, Purvi Majethia, Rory J. Olson, Karthik Muthusamy, Lisa A. Schimmenti, Keith Starnes, Lucie Sedláčková, Katalin Štěrbová, Markéta Vlčková, Petra Laššuthová, Alena Jahodová, Brenda E. Porter, Nathalie Couque, Estelle Colin, Clément Prouteau, Corinne Collet, Thomas Smol, Roseline Caumes, Fleur Vansenne, Francesca Bisulli, Laura Licchetta, Richard Person, Erin Torti, Kirsty McWalter, Richard Webster, Elizabeth E. Gerard, Gaetan Lesca, Pierre Szepetowski, Ingrid E. Scheffer, Heather C. Mefford, Gemma L. Carvill, University of Otago [Dunedin, Nouvelle-Zélande], University of Washington [Seattle], Epilepsy Research Centre, University of Melbourne, Duke University Medical Center, Institute for Genomic Medicine [New York, NY, USA], Columbia University [New York], Columbia University Irving Medical Center (CUIMC), University of Southern Denmark (SDU), Zealand University Hospital [Roskilde, Denmark], University of British Columbia [Vancouver], University College Dublin [Dublin] (UCD), Kasturba Medical College, Manipal, Center for Individualized Medicine, Stanford University School of Medicine [CA, USA], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Bologna/Università di Bologna, GeneDx [Gaithersburg, MD, USA], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurology (clinical), Research Article
Abstract: Background and ObjectivesKCNH5encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novoKCNH5variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies forKCNH5variants using targeted or exome sequencing. Additional individuals withKCNH5variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establishKCNH5as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
Published: 2022

9. Control of Ca 2+ signals by astrocyte nanoscale morphology at tripartite synapses

Author: Audrey Denizot, Misa Arizono, U. Valentin Nägerl, Hugues Berry, Erik De Schutter, Okinawa Institute of Science and Technology Graduate University (OIST), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Artificial Evolution and Computational Biology (BEAGLE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)
Subjects: Cellular and Molecular Neuroscience, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, intracellular signaling, calcium microdomains, reaction–diffusion simulations, nano-morphology, computational neuroscience
Abstract: International audience; Much of the Ca2+ activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain. A growing body of literature indicates that those astrocytic Ca2+ signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca2+ microdomain activity remains poorly understood. Here, we use computational tools and idealized 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+ signals and promotes local Ca2+ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre- and postsynaptic structures.
Published: 2022

10. State‐of‐the‐art therapies for Rett syndrome

Author: Nicolas Panayotis, Yann Ehinger, Marie Solenne Felix, Jean‐Christophe Roux, Université Paris Cité (UPCité), Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Aix Marseille University, grants from theAFM-Téléthon(Strategic pole MNH Decrypt), PromexStiftung Für Die Forschung, Retts yndro me.org (IRSF) andAssociation Française du Syndrome de Rett., and Weizmann Institute of Science [Rehovot, Israël]
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Developmental Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Pediatrics, Perinatology and Child Health, Neurology (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome.
Published: 2022

11. Phenotypic characterization of seven individuals with <scp>Marbach–Schaaf</scp> neurodevelopmental syndrome

Author: Felix Marbach, Beata S. Lipska‐Ziętkiewicz, Agata Knurowska, Vincent Michaud, Henri Margot, James Lespinasse, Frédéric Tran Mau Them, Christine Coubes, Joohyun Park, Sarah Grosch, Cristiana Roggia, Ute Grasshoff, Louisa Kalsner, Anne‐Sophie Denommé‐Pichon, Alexandra Afenjar, Bénédicte Héron, Boris Keren, Pilar Caro, Christian P. Schaaf, Heidelberg University, University of Gdańsk (UG), Medical University of Gdańsk, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Tübingen, School of Medicine [University of Connecticut], University of Connecticut (UCONN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Baylor College of Medicine (BCM), Baylor University, and Admin, Oskar
Subjects: Adult, Pain insensitivity, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Global developmental delay, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Syndrome, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Cohort Studies, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Phenotype, Neurodevelopmental disorder, PRKAR1B, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Genetics, Protein kinase a complex, Animals, Humans, Genetics (clinical)
Abstract: International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.
Published: 2022

12. Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring

Author: Jean Nakhle, Khattar Khattar, Tülin Özkan, Adel Boughlita, Daouda Abba Moussa, Amelie Darlix, Frédérique Lorcy, Valérie RIGAU, Luc BAUCHET, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Floriant Bellvert, Laurent Turchi, Thierry Virolle, Jean-Philippe Hugnot, Nicolas Buisine, Mireille Galloni, Valerie Dardalhon, Anne-Marie Rodriguez, Marie-Luce Vignais, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Ankara University School of Medicine [Turkey], Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Hôpital Gui de Chauliac [CHU Montpellier], Neurochirurgie [Hôpital Gui de Chauliac], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Physiologie moléculaire et adaptation (PhyMA), Muséum national d'Histoire naturelle (MNHN)-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), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), 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), ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), Institut de recherche en biothérapie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuroradiologie [Hôpital Gui de Chauliac], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Abstract: International audience; Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.
Published: 2023

13. Neuronal Store-Operated Calcium Channels

Author: Alexandre Bouron, Genetics and Chemogenomics (GenChem), Laboratoire Biosciences et bioingénierie pour la santé (BGE), 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)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), and Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038)
Subjects: Cellular and Molecular Neuroscience, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuroscience (miscellaneous)
Abstract: International audience; The endoplasmic reticulum (ER) is the major intracellular calcium (Ca2+) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca2+ from this store is followed by a delayed and sustained uptake of Ca2+ through Ca2+-permeable channels of the cell surface named store-operated Ca2+ channels (SOCCs). This gives rise to a store-operated Ca2+ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca2+ entry pathway. The existence of this Ca2+ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca2+ from neuronal ER Ca2+ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca2+ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.
Published: 2023

14. Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory

Author: Eléonore Hardy, Julien Moulard, Augustin Walter, Pascal Ezan, Alexis-Pierre Bemelmans, Franck Mouthon, Mathieu Charvériat, Nathalie Rouach, Armelle Rancillac, 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), Université Paris sciences et lettres (PSL), Ecole doctorale Cerveau Cognition et Comportement [Paris] (ED 158 - 3C), Sorbonne Université (SU), 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), Theranexus [Lyon], and Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris)
Subjects: General Immunology and Microbiology, General Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; Astrocytes crucially contribute to synaptic physiology and information processing. One of their key characteristics is to express high levels of connexins (Cxs), the gap junction–forming protein. Among them, Cx30 displays specific properties since it is postnatally expressed and dynamically upregulated by neuronal activity and modulates cognitive processes by shaping synaptic and network activities, as recently shown in knockout mice. However, it remains unknown whether local and selective upregulation of Cx30 in postnatal astrocytes within a physiological range modulates neuronal activities in the hippocampus. We here show in mice that, whereas Cx30 upregulation increases the connectivity of astroglial networks, it decreases spontaneous and evoked synaptic transmission. This effect results from a reduced neuronal excitability and translates into an alteration in the induction of synaptic plasticity and an in vivo impairment in learning processes. Altogether, these results suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.
Published: 2023

15. Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero

Author: Maria Llach Pou, Camille Thiberge, Michiel Van der Zwan, Annousha Devi Govindan, Stéphanie Pons, Uwe Maskos, Isabelle Cloëz-Tayarani, Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), France Fondation Alzheimer, Fondation Vaincre Alzheimer, ADPS-Allianz, Equipe 2019, Projet Explore 2021, Fondation pour la Recherche sur Alzheimer, Pasteur-Paris University (PPU) international doctoral program, MDPI, and ANR-17-NEU3-0004,iPS_BRAIN,A functional dissection of human nicotinic receptor polymorphisms linked to addiction and schizophrenia(2017)
Subjects: xenografting, in utero transplant, human stem cells, human-induced pluripotent stem cells, chimeric mouse models, brain development, brain disorders, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Medicine
Abstract: International audience; The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the embryonic stages, in utero, with unique properties at its neotenic stages. We analyzed the engraftment and differentiation of human neuronal progenitor cells (hNPCs) transplanted in utero into the mouse brain. The influence of the environment was studied by transplanting human NPCs within the lateral ventricles (LV), compared with the prefrontal cortex (PFC) of immunocompetent mice. We developed a semi-automated method to accurately quantify the number of cell bodies and the distribution of neuronal projections among the different mouse brain structures, at 1 and 3 months post-transplantation (MPT). Our data show that human NPCs can differentiate between immature “juvenile” neurons and more mature pyramidal cells in a reproducible manner. Depending on the injection site, LV vs. PFC, specific fetal local environments could modify the synaptogenesis processes while maintaining human neoteny. The use of immunocompetent mice as host species allows us to investigate further neuropathological conditions making use of all of the engineered mouse models already available.
Published: 2023

16. Identification of the three zinc-binding sites on tau protein

Author: Pascale Barbier, François Devred, Françoise Guerlesquin, Diane Allegro, Malesinski Soazig, Romain La Rocca, Andrey V. Golovin, Philipp O. Tsvetkov, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Lomonosov Moscow State University (MSU), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Gene isoform, Zinc binding, Binding sites, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Tau protein, chemistry.chemical_element, tau Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Zinc, Microtubules, Biochemistry, Dynamic light scattering, Structural Biology, Humans, Binding site, Cytoskeleton, Molecular Biology, biology, Isothermal titration calorimetry, General Medicine, NMR, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, chemistry, Tauopathies, biology.protein, Biophysics, Tau, Protein Binding
Abstract: Tau protein has been extensively studied due to its key roles in microtubular cytoskeleton regulation and in the formation of aggregates found in some neurodegenerative diseases. Recently it has been shown that zinc is able to induce tau aggregation by interacting with several binding sites. However, the precise location of these sites and the molecular mechanism of zinc-induced aggregation remain unknown. Here we used Nuclear Magnetic Resonance (NMR) to identify zinc binding sites on hTau40 isoform. These experiments revealed three distinct zinc binding sites on tau, located in the N-terminal part (H14, H32, H94, and H121), the repeat region (H299, C322, H329 and H330) and the C-terminal part (H362, H374, H388 and H407). Further analysis enabled us to show that the C-terminal and the N-terminal sites are independent of each other. Using molecular simulations, we modeled the structure of each site in a complex with zinc. Given the clinical importance of zinc in tau aggregation, our findings pave the way for designing potential therapies for tauopathies.HighlightsZinc is known to induce tau aggregation in neurodegenerative diseasesZinc binding locations and mechanism are not yet clearUsing NMR we localized 3 zinc binding site on tauBy molecular simulations, we proposed a modeled structure of each siteOur findings pave the way for designing potential therapies for tauopathies
Published: 2022

17. Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies

Author: Martins, D., Dipasquale, O., Davies, K., Cooper, E., Tibble, J., Veronese, M., Frigo, M., Williams, S.C.R., Turkheimer, F., Cercignani, M., Harrison, N.A., King‘s College London, University of Sussex, Brighton and Sussex University Hospitals - NHS Trust (BSUH), Department of Information Engineering [Padova] (DEI), Università degli Studi di Padova = University of Padua (Unipd), Computational Imaging of the Central Nervous System (ATHENA), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Cardiff University's Brain Research Imaging Centre [Cardiff] (CUBRIC), School of Psychology [Cardiff University], Cardiff University-Cardiff University, Cardiff University, DM, OD, MV, FET and SCRM are supported by the NIHR Maudsley’s Biomedical Research Centre at the South London and Maudsley NHS Trust. MF is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC Advanced Grant agreement No 694665: CoBCoM - Computational Brain Connectivity Mapping)., and European Project: 694665,H2020 ERC,ERC-2015-AdG,CoBCoM(2016)
Subjects: Inflammation, Depression, Endocrine and Autonomic Systems, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunology, Anti-Inflammatory Agents, Brain, Interferon-alpha, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Transcriptomic vulnerability, global brain connectivity, Anti-TNF, Behavioral Neuroscience, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, Tumor Necrosis Factor Inhibitors, Imaging transcriptomics, Transcriptome, Interferon-α
Abstract: Background\ud Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood.\ud \ud Methods\ud We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment.\ud \ud Results\ud Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms.\ud \ud Conclusions\ud Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.
Published: 2022

18. Developmental programming of hypothalamic melanocortin circuits

Author: Sebastien G. Bouret, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, and Bouret, Sebastien
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, endocrine system, Pro-Opiomelanocortin, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, digestive, oral, and skin physiology, Clinical Biochemistry, Hypothalamus, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Biochemistry, Melanocortins, nervous system, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Humans, Molecular Medicine, Agouti-Related Protein, Obesity, Peptides, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, hormones, hormone substitutes, and hormone antagonists
Abstract: The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.
Published: 2022

19. Efficacy of Caffeine in <scp>ADCY5</scp> ‐Related Dyskinesia: A Retrospective Study

Author: Aurélie Méneret, Shekeeb S. Mohammad, Laura Cif, Diane Doummar, Claudio DeGusmao, Mathieu Anheim, Magalie Barth, Philippe Damier, Nathalie Demonceau, Jennifer Friedman, Cécile Gallea, Domitille Gras, Juliana Gurgel‐Giannetti, Emily A. Innes, Ján Necpál, Florence Riant, Sandrine Sagnes, Catherine Sarret, Yury Seliverstov, Vijayashankar Paramanandam, Kuldeep Shetty, Christine Tranchant, Mohamed Doulazmi, Marie Vidailhet, Tamara Pringsheim, Emmanuel Roze, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of California [San Diego] (UC San Diego), University of California (UC), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Observatoire National Français des patients atteints de DMFSH (FSHD registry - France), Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Dyskinesias, Movement Disorders, Neurology, Caffeine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Humans, Neurology (clinical), Child, Adenylyl Cyclases, Retrospective Studies
Abstract: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine.The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia.A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire.Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening.Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
Published: 2022

20. Role of the deubiquitinating enzyme UCH-L1 in mitochondrial function

Author: Alexandre Bouron, Laurence Aubry, Desirée Loreth, Marie-Odile Fauvarque, Catherine Meyer-Schwesinger, Genetics and Chemogenomics (GenChem), Laboratoire Biosciences et bioingénierie pour la santé (BGE), 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)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), and Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038)
Subjects: MESH: mitochondria, MESH: pathology, Cellular and Molecular Neuroscience, MESH: neurodegeneration, MESH: brain, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: deubiquitinating enzymes, MESH: UCH-L1
Abstract: International audience
Published: 2023

21. Haslea ostrearia Pigment Marennine Affects Key Actors of Neuroinflammation and Decreases Cell Migration in Murine Neuroglial Cell Model

Author: Sarah Méresse, Hélène Gateau, Tessa Tirnan, Vanessa Larrigaldie, Nathalie Casse, Pamela Pasetto, Jean-Luc Mouget, Stéphane Mortaud, Mostefa Fodil, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), BIOlogie des populations, Stress, Santé, Environnement (BIOSSE), Université Catholique de l'Ouest (UCO), Institut des Molécules et Matériaux du Mans (IMMM), Le Mans Université (UM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), FEDER N°EX016008 TARGET-EX, GHaNA (The Genus Haslea, New marine resources for blue biotechnology and Aquaculture) 734708/GHANA/H2020-MSCA-RISE-2016, and European Project: EX016008,TARGET-EX
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Chemistry, General Medicine, migration, biomolecules, Catalysis, diatoms, neuroinflammation, Computer Science Applications, Inorganic Chemistry, Haslea ostrearia, marennine, neuroglial cells, immunostimulation, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; Haslea ostrearia, a cosmopolitan marine pennate diatom, produces a characteristic blue pigment called marennine that causes the greening of filter-feeding organisms, such as oysters. Previous studies evidenced various biological activities of purified marennine extract, such as antibacterial, antioxidant and antiproliferative effects. These effects could be beneficial to human health. However, the specific biological activity of marennine remains to be characterized, especially regarding primary cultures of mammals. In the present study, we aimed to determine in vitro the effects of a purified extract of marennine on neuroinflammatory and cell migratory processes. These effects were assessed at non-cytotoxic concentrations of 10 and 50μg/mL on primary cultures of neuroglial cells. Marennine strongly interacts with neuroinflammatory processes in the immunocompetent cells of the central nervous system, represented by astrocytes and microglial cells. An anti-migratory activity based on a neurospheres migration assay has also been observed. These results encourage further study of Haslea blue pigment effects, particularly the identification of molecular and cellular targets affected by marennine, and strengthen previous studies suggesting that marennine has bioactivities which could be beneficial for human health applications.
Published: 2023
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22. Interpretable automatic detection of incomplete hippocampal inversions using anatomical criteria

Author: Hemforth, Lisa, Cury, Claire, Frouin, Vincent, Desrivières, Sylvane, Grigis, Antoine, Garavan, Hugh, Brühl, Rüdiger, Martinot, Jean-Luc, Paillère Martinot, Marie-Laure, Artiges, Eric, Poustka, Luise, Hohmann, Sarah, Millenet, Sabina, Vaidya, Nilakshi, Walter, Henrik, Whelan, Robert, Schumann, Gunter, Couvy-Duchesne, Baptiste, Colliot, Olivier, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), Neuroimagerie: méthodes et applications (EMPENN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAL, IMAGE ET LANGAGE (IRISA-D6), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), 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), King‘s College London, University of Vermont [Burlington], Physikalisch-Technische Bundesanstalt [Berlin] (PTB), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), EPS Barthélemy Durand [Etampes], University Medical Center Göttingen (UMG), University Hospital Mannheim | Universitätsmedizin Mannheim, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Trinity College Dublin, Fudan University [Shanghai], Institut du Cerveau = Paris Brain Institute (ICM), 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), University of Queensland [Brisbane], ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-12-SAMA-0004,ADODEP,Dépression à l'Adolescence: Structure cérébrale et myélinisation(2012), ANR-19-CE37-0017,GeBra,Approches translationelles, profilage transcriptomique, et imagerie cérébrale: vers des nouveaux biomarqueurs et réseaux biologiques dans la resilience au stress(2019), ANR-18-NEUR-0002,ADORe,TARGETING ADOLESCENT NEUROCOGNITIVE PROCESSES IN DEPRESSION TO PROMOTE INTERVENTION RESPONSE(2018), European Project: 351475,NHMRC::NHMRC Project Grants(2005), European Project: 695313,STRATIFY, European Project: 785907,H2020,HBP SGA2(2018), and European Project: 945539,H2020,H2020-SGA-FETFLAG-HBP-2019,HBP SGA3(2020)
Subjects: Deep Learning 3D, Machine Learning, Deep Learning, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Incomplete Hippocampal Inversion, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Hippocampus, MRI, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience; Incomplete Hippocampal Inversion (IHI) is an atypical anatomical pattern of the hippocampus that has been associated with several brain disorders (epilepsy, schizophrenia). IHI can be visually detected on coronal T1 weighted MRI images. IHI can be absent, partial or complete (no IHI, partial IHI, IHI). However, visual evaluation can be long and tedious, justifying the need for an automatic method. In this paper, we propose, to the best of our knowledge, the first automatic IHI detection method from T1-weighted MRI. The originality of our approach is that, instead of directly detecting IHI, we propose to predict several anatomical criteria, which each characterize a particular anatomical feature of IHI, and that can ultimately be combined for IHI detection. Such individual criteria have the advantage of providing interpretable anatomical information regarding the morphological aspect of a given hippocampus. We relied on a large population of 2,008 participants from the IMAGEN study. The approach is general and can be used with different machine learning models. In this paper, we explored two different backbone models for the prediction: a linear method (ridge regression) and a deep convolutional neural network. We demonstrated that the interpretable, anatomical based prediction was at least as good as when predicting directly the presence of IHI, while providing interpretable information to the clinician or neuroscientist. This approach may be applied to other diagnostic tasks which can be characterized radiologically by several anatomical features.
Published: 2023

23. Neuronal Blockade of Thyroid Hormone Signaling Increases Sensitivity to Diet-Induced Obesity in Adult Male Mice

Author: Eva Rial-Pensado, Laurence Canaple, Romain Guyot, Christoffer Clemmensen, Joëlle Wiersema, Shijia Wu, Sabine Richard, Anita Boelen, Timo D Müller, Miguel López, Frédéric Flamant, Karine Gauthier, Universidade de Santiago de Compostela [Spain] (USC ), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Amsterdam [Amsterdam] (UvA), Endocrinology Laboratory, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development
Subjects: Thyroid hormone, Endocrinology, diet-induced obesity, sympathetic nervous system (SNS), diet induced obesity, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, adaptive thermogenesis, cold exposure, neurons, brown adipose tissue, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract: Thyroid hormone increases energy expenditure. Its action is mediated by TR, nuclear receptors present in peripheral tissues and in the central nervous system, particularly in hypothalamic neurons. Here, we address the importance of thyroid hormone signaling in neurons, in general for the regulation of energy expenditure.We generated mice devoid of functional TR in neurons using the Cre/LoxP system. In hypothalamus, which is the center for metabolic regulation, mutations were present in 20% to 42% of the neurons.Phenotyping was performed under physiological conditions that trigger adaptive thermogenesis: cold and high-fat diet (HFD) feeding. Mutant mice displayed impaired thermogenic potential in brown and inguinal white adipose tissues and were more prone to diet-induced obesity. They showed a decreased energy expenditure on chow diet and gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue of the mutants. In contrast, absence of TR signaling in the mutants did not affect their ability to respond to cold exposure.This study provides the first genetic evidence that thyroid hormone signaling exerts a significant influence in neurons to stimulate energy expenditure in some physiological context of adaptive thermogenesis. TR function in neurons to limit weight gain in response to HFD and this effect is associated with a potentiation of SNS output.
Published: 2023

24. Temporal pattern recognition in retinal ganglion cells is mediated by dynamical inhibitory synapses

Author: Simone Ebert, Thomas Buffet, B.Semihcan Sermet, Olivier Marre, Bruno Cessac, Biologically plausible Integrative mOdels of the Visual system : towards synergIstic Solutions for visually-Impaired people and artificial visiON (BIOVISION), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Académie Systèmes Complexes, Complex Systems Academy, COMPLEX SYSTEMS ACADEMY, ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), Neuromod Institute, and Université Côte d'Azur (UCA)
Subjects: Computational Neuroscience, Short-term Plasticity, [SCCO]Cognitive science, Vision, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Biophysics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Dynamical Systems, Inhibition
Abstract: A fundamental task for the brain is to generate predictions of future sensory inputs, and signal errors in these predictions. Many neurons have been shown to signal omitted stimuli during periodic stimulation, even in the retina. However, the mechanisms of this error signaling are unclear. Here we show that depressing inhibitory synapses enable the retina to signal an omitted stimulus in a flash sequence. While ganglion cells, the retinal output, responded to an omitted flash with a constant latency over many frequencies of the flash sequence, we found that this was not the case once inhibition was blocked. We built a simple circuit model and showed that depressing inhibitory synapses were a necessary component to reproduce our experimental findings. We also generated new predictions with this model, that we confirmed experimentally. Depressing inhibitory synapses could thus be a key component to generate the predictive responses observed in many brain areas.
Published: 2023

25. HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer's disease

Author: Marie Alexandra Albaret, Julien Textoris, Bastien Dalzon, Jérémy Lambert, Morgane Linard, Catherine Helmer, Sabine Hacot, Sandra E. Ghayad, Martial Ferréol, Hichem C. Mertani, Jean-Jacques Diaz, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Department of Translational Research and Innovation [Lyon], Centre Léon Bérard [Lyon], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Protéomique pour la Microbiologie, l'Immunologie et la Toxicologie (PROMIT), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-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)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Grenoble Alpes (UGA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), RiverLy - Fonctionnement des hydrosystèmes (RiverLy), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Convergence PLAsCAN, LYON
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Biological Psychiatry
Abstract: International audience; Many studies highlight the potential link between the chronic degenerative Alzheimer's disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer's disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (A beta 42) oligomers followed by their accumulation in neuronal cells. A beta 42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer's disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer's disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of A beta 42 production characteristic of Alzheimer's disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced A beta 42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer's disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of A beta 42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer's disease stages leading to a chronic amplification of A beta 42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer's disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors.
Published: 2023

26. CSF-contacting neurons respond to Streptococcus pneumoniae and promote host survival during central nervous system infection

Author: Andrew E. Prendergast, Kin Ki Jim, Hugo Marnas, Laura Desban, Feng B. Quan, Lydia Djenoune, Valerio Laghi, Agnès Hocquemiller, Elias T. Lunsford, Julian Roussel, Ludovic Keiser, Francois-Xavier Lejeune, Mahalakshmi Dhanasekar, Pierre-Luc Bardet, Jean-Pierre Levraud, Diederik van de Beek, Christina M.J.E. Vandenbroucke-Grauls, Claire Wyart, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Amsterdam [Amsterdam] (UvA), Vrije Universiteit Amsterdam [Amsterdam] (VU), Amsterdam institute for Infection and Immunity [Amsterdam, The Netherlands] (A3I), Macrophages et Développement de l’Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Fondation Schlumberger pour l’Education et la Recherche (FSER/2017), the Fondation pour la Recherche Médicale (FRM no. Equation 202003010612), the ERC Starting Grant 'Optoloco' no. 311673, ERC PoC 'ZebraZoom' no. 825273, and ERC Consolidator Grant 'Exploratome' no. 101002870 (to C.W.). We acknowledge support from 'MeninGene' no. 281156 and the HFSP Program grant nos. RGP0063/2014 and RGP0063/2017 and grants from the Agence Nationale de la Recherche (ANR) ASCENTS no. ANR-21-CE13-0008, MOTOMYO no. ANR-21-CE14-0042, and ANR LOCOCONNECT no. ANR-22-CE37-0023 et la Fondation Bettencourt-Schueller don 0031. D.v.d.B. was supported by a ZonMw VICI grant no. 391819627. A.E.P. was supported by an EMBO long-term fellowship (ALTF-549-2013) and a Research in Paris grant from the Marie de Paris. L. Desban was supported by the French Ministry of Higher Education and Research doctoral fellowship. M.D. was supported by a PhD fellowship from the Sorbonne Université Ecole Doctorale ED3C., ANR-21-CE13-0008,ASCENTS,Étude d'une asymétrie structurelle nouvellement identifiée du centriole des vertébrés et de son impact sur le développement et la santé(2021), ANR-21-CE14-0042,MOTOMYO,Appariement entre sous types de motoneurones et sous types de myofibres: du développement à la pathologie(2021), ANR-22-CE37-0023,LOCONNECT,Transmission d'information causale lors de la locomotion(2022), European Project: 311673,EC:FP7:ERC,ERC-2012-StG_20111109,OPTOLOCO(2013), Medical Microbiology and Infection Prevention, AII - Infectious diseases, AII - Inflammatory diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, ANS - Neuroinfection & -inflammation, and Neurology
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, in-situ hybridization, interoception, substance inducing transformation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, General Biochemistry, Genetics and Molecular Biology, cerebrospinal fluid, volatile metabolites, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, central nervous system infection, innate immunity, cytolysins, solitary chemosensory cells, pneumococcal types, chemical nature, zebrafish, gene-expression, pathogen detection, cerebrospinal-fluid, cytokines, sensory neurons, host defense, peptides, taste receptors, neurosecretion, General Agricultural and Biological Sciences, bacterial meningitis, bitter compounds
Abstract: International audience; The pathogenic bacterium Streptococcus pneumoniae (S. pneumoniae) can invade the cerebrospinal fluid (CSF) and cause meningitis with devastating consequences. Whether and how sensory cells in the central nervous system (CNS) become activated during bacterial infection, as recently reported for the peripheral nervous system, is not known. We find that CSF infection by S. pneumoniae in larval zebrafish leads to changes in posture and behavior that are reminiscent of pneumococcal meningitis, including dorsal arching and epileptic-like seizures. We show that during infection, invasion of the CSF by S. pneumoniae massively activates in vivo sensory neurons contacting the CSF, referred to as “CSF-cNs” and previously shown to detect spinal curvature and to control posture, locomotion, and spine morphogenesis. We find that CSF-cNs express orphan bitter taste receptors and respond in vitro to bacterial supernatant and metabolites via massive calcium transients, similar to the ones observed in vivo during infection. Upon infection, CSF-cNs also upregulate the expression of numerous cytokines and complement components involved in innate immunity. Accordingly, we demonstrate, using cell-specific ablation and blockade of neurotransmission, that CSF-cN neurosecretion enhances survival of the host during S. pneumoniae infection. Finally, we show that CSF-cNs respond to various pathogenic bacteria causing meningitis in humans, as well as to the supernatant of cells infected by a neurotropic virus. Altogether, our work uncovers that central sensory neurons in the spinal cord, previously involved in postural control and morphogenesis, contribute as well to host survival by responding to the invasion of the CSF by pathogenic bacteria during meningitis.
Published: 2023

27. Impact of sex and APOE-ε4 genotype on patterns of regional brain atrophy in Alzheimer's Disease and healthy ageing

Author: Benoît Sauty, Stanley Durrleman, Sauty, Benoît, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Early Detection of Alzheimer's Disease Subtypes - - E-DADS2019 - ANR-19-JPW2-0002 - JPND - VALID, Learning spatiotemporal patterns in longitudinal image data sets of the aging brain - LEASP - - H2020 ERC2016-09-01 - 2021-08-31 - 678304 - VALID, VirtualBrainCloud - TVB-Cloud - 2018-12-01 - 2022-11-30 - 826421 - VALID, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), 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), Sorbonne Université (SU), This work was funded in part by the French government under management of Agence Nationale de la Recherche as part of the 'Investissements d’avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute), ANR-19-JPW2-000 (E-DADS) and ANR10-IAIHU-06 (IHU ICM), as well as by the European Research council reference ERC-678304 and the H2020 programme via grant 826421 (TVB-Cloud)., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-19-JPW2-0002,E-DADS,Early Detection of Alzheimer's Disease Subtypes(2019), European Project: 678304,H2020 ERC,ERC-2015-STG,LEASP(2016), and European Project: 826421,TVB-Cloud (2018)
Subjects: [STAT.AP]Statistics [stat]/Applications [stat.AP], Brain atrophy, Sexual dimorphism, Ageing, [STAT.AP] Statistics [stat]/Applications [stat.AP], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Longitudinal studies, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Alzheimer's Disease, Genetic covariates, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Purpose: Alzheimer’s Disease (AD) is a heterogeneous disease that disproportionately affects women and people with the APOE-ε4 susceptibility gene. We aim to describe the not-well-understood influence of both risk factors on the dynamics of brain atrophy in AD and healthy aging.Approach: Regional cortical thinning and brain atrophy were modeled over time using non-linear mixed-effect models and the FreeSurfer software. Covariance analysis was used to disentangle the effect of sex and APOE genotype on the regional onset age and pace of atrophy, while correcting for educational level. A map of the regions most affected by neurodegeneration is provided. Results were confirmed on gray matter density data from the SPM software.Results: Women experience faster atrophic rates in the temporal, frontal, parietal lobes and limbic system and earlier onset in the amygdalas, but slightly later onset in the postcentral and cingulate gyri as well as all regions of the basal ganglia and thalamus. APOE-ε4 genotypes leads to earlier and faster atrophy in the temporal, frontal, parietal lobes and limbic system in AD patients, but not in healthy patients. Higher education was found to slightly delay atrophy in healthy patients, but not for AD patients. A cohort of amyloid positive patients with MCI showed a similar impact of sex as in the healthy cohort, while APOE-ε4 showed similar associations as in the AD cohort.Conclusion: Female sex is as strong a risk factor for AD as APOE−ε4 genotype regarding neurodegeneration, women experience a sharper atrophy in the later stages of the disease although not a significantly earlier onset. These findings may have important implications for the development of targeted intervention.
Published: 2023

28. Secretion of VGF relies on the interplay between LRRK2 and post-Golgi v-SNAREs

Author: Francesca Filippini, Sébastien Nola, Ahmed Zahraoui, Kevin Roger, Mansoore Esmaili, Ji Sun, José Wojnacki, Anaïs Vlieghe, Philippe Bun, Stéphanie Blanchon, Jean-Christophe Rain, Jean-Marc Taymans, Marie-Christine Chartier-Harlin, Chiara Guerrera, Thierry Galli, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and ANR-16-CE16-0012,MeTDePaDi,Défauts de Traffic Membranaire dans la Maladie de Parkinson(2016)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; The neuropeptide VGF was recently proposed as a neurodegeneration biomarker. The Parkinson’s disease-related protein leucine-rich repeat kinase 2 (LRRK2) regulates endolysosomal dynamics, a process that involves SNARE-mediated membrane fusion and could regulate secretion. Here we investigate potential biochemical and functional links between LRRK2 and v-SNAREs. We find that LRRK2 directly interacts with the v-SNAREs VAMP4 and VAMP7. Secretomics reveals VGF secretory defects in VAMP4 and VAMP7 knockout (KO) neuronal cells. In contrast, VAMP2 KO “regulated secretion-null” and ATG5 KO “autophagy-null” cells release more VGF. VGF is partially associated with extracellular vesicles and LAMP1+ endolysosomes. LRRK2 expression increases VGF perinuclear localization and impairs its secretion. Retention using selective hooks (RUSH) assays show that a pool of VGF traffics through VAMP4+ and VAMP7+ compartments, and LRRK2 expression delays its transport to the cell periphery. Overexpression of LRRK2 or VAMP7-longin domain impairs VGF peripheral localization in primary cultured neurons. Altogether, our results suggest that LRRK2 might regulate VGF secretion via interaction with VAMP4 and VAMP7
Published: 2023

29. L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus

Author: Marie-Elisa Pinson, Franck Court, Aymeric Masson, Yoan Renaud, Allison Fantini, Ophélie Bacoeur-Ouzillou, Marie Barriere, Bruno Pereira, Pierre-Olivier Guichet, Emmanuel Chautard, Lucie Karayan-Tapon, Pierre Verrelle, Philippe Arnaud, Catherine Vaurs-Barrière, BARRIERE, Catherine, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie [Paris], Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Retroelements, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma, General Medicine, Long Interspersed Nucleotide Elements, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Promoter Regions, Genetic, Molecular Biology, Genetics (clinical)
Abstract: Besides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5′ UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand.
Published: 2022

30. Begging and feeding responses vary with relatedness and sex of provisioners in a cooperative breeder

Author: Rita Fortuna, Pietro B. D'Amelio, Claire Doutrelant, André C. Ferreira, Clothilde Lecq, Liliana R. Silva, Rita Covas, Fanny Rybak, Matthieu Paquet, Universidade do Porto = University of Porto, Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), University of Cape Town, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Swedish University of Agricultural Sciences (SLU), and ANR-19-CE02-0014,EXTENDEDPHENOTYPE,L'évolution des phénotypes L'évolution des phénotypes étendus et signaux associés chez les animaux: les nids de tisserins et la sélection sexuelle en tant que cas d'étude(2019)
Subjects: [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Begging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parent-offspring interactions, Animal Science and Zoology, Sociable weaver, Zoology, Helpers, Ecology, Evolution, Behavior and Systematics, Cooperative breeding, Feeding responses
Abstract: Begging behaviour can provide information on offspring hunger levels and be used by parents to adjust food provisioning efforts. In cooperative breeders, helpers also provide care by feeding the young. However, how helpers of different sex and relatedness to the offspring respond to begging behaviour has rarely been studied in cooperatively breeding species, which limits our understanding of the indirect and/or direct benefits that helpers may obtain by responding to offspring demand. Here, we used a cooperatively breeding bird, the sociable weaver, Philetairus socius, to investigate how nest intervisit intervals of breeders and different types of helpers, distinguished by sex and relatedness, varied with acoustic begging. Moreover, we tested whether these different classes of provisioners experienced distinct levels of begging. Our results show that only breeding males, but not breeding females or helpers of any sex and relatedness to the nestlings, returned faster to the nest to feed after experiencing more begging calls. When contrasted directly, we confirmed a statistically supported difference in responses to begging between male and female breeders. Surprisingly, second-order relatives experienced more begging calls than the other classes of more related helpers and breeders. These results show that we might find differences in how provisioners respond to begging levels when classifying group members according to their potential fitness gains. In sociable weavers, the benefits and costs of adjusting feeding efforts to begging seem to differ with sex and life history stage. Experimental and more detailed investigations on begging-feeding interactions are necessary to understand the origin and prevalence of these differences across cooperatively breeding systems. (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of The Association for the Study of Animal Behaviour. This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/).
Published: 2022

31. CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress

Author: Jérémy Sitbon, Dennis Nestvogel, Caroline Kappeler, Aude Nicolas, Stephanie Maciuba, Annabelle Henrion, Réjane Troudet, Elisa Courtois, Gaël Grannec, Violaine Latapie, Caroline Barau, Philippe Le Corvoisier, Nicolas Pietrancosta, Chantal Henry, Marion Leboyer, Bruno Etain, Marika Nosten-Bertrand, Thomas F. J. Martin, JeongSeop Rhee, Stéphane Jamain, 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), Fondation FondaMental [Créteil], Max Planck Institute of Experimental Medicine [Göttingen] (MPI), Max-Planck-Gesellschaft, University of Wisconsin-Madison, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme de Ressources Biologiques [Henri Mondor AP-HP, Créteil] (PRB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Université Sorbonne Paris Cité (USPC), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'NeuroPsychologie Interventionnelle' [Créteil] (U955 Inserm - UPEC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS 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), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), 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 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), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), 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)-Chimie Moléculaire de Paris Centre (FR 2769), and Jamain, Stéphane
Subjects: Bipolar Disorder, Neuronal Plasticity, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Calcium-Binding Proteins, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vesicular Transport Proteins, Nerve Tissue Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Exocytosis, Mice, Cellular and Molecular Neuroscience, Psychiatry and Mental health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Mutation, Animals, Humans, Calcium, Molecular Biology
Abstract: International audience; Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps+/- revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.
Published: 2022

32. Mitochondrial transport, partitioning, and quality control at the heart of cell proliferation and fate acquisition

Author: Giulia Bertolin, Rakesh Kumar Sharma, Abderrahman Chafik, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), SAD grant, Region Bretagne, Centre National de la Recherche Scientifique, Fondation ARC pour la Recherche sur le Cancer, and Grand Ouest grant, Ligue Contre le Cancer
Subjects: Physiology, [SDV]Life Sciences [q-bio], Cellular differentiation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, Mitochondrial Dynamics, Mitochondria, Heart, Yeasts, Mitophagy, medicine, anatomy_morphology, Animals, Homeostasis, Humans, Cell Lineage, Myocytes, Cardiac, Mitochondrial transport, Cell growth, Biological Transport, Cell Differentiation, dynamics, Cell Biology, Cell cycle, Cell biology, mitochondria, fate acquisition, medicine.anatomical_structure, Phenotype, transport, Energy Metabolism
Abstract: International audience; Mitochondria are essential to cell homeostasis, and alterations in mitochondrial distribution, segregation, and turnover have been linked to complex pathologies such as neurodegenerative diseases and cancer. Understanding how these functions are coordinated in specific cell types is a major challenge to discover how mitochondria globally shape cell functionality. In this review, we first describe how mitochondrial transport and dynamics are regulated throughout the cell cycle in yeast and in mammals. Second, we explore the functional consequences of mitochondrial transport and partitioning on cell proliferation, fate acquisition, and stemness and on the way cells adapt their metabolism. Finally, we focus on how mitochondrial clearance programs represent a further layer of complexity for cell differentiation or in the maintenance of stemness. Defining how mitochondrial transport, dynamics, and clearance are mutually orchestrated in specific cell types may help our understanding of how cells can transition from a physiological to a pathological state.
Published: 2022

33. Inhibitors of ectonucleotidases have paradoxical effects on synaptic transmission in the mouse cortex

Author: Marie Gleizes, Caroline Fonta, Lionel G. Nowak, Centre de recherche cerveau et cognition (CERCO UMR5549), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, and Fonta, Caroline
Subjects: ALPL, Adenosine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Synaptic Transmission, Biochemistry, Mice, Cellular and Molecular Neuroscience, Adenosine Triphosphate, Nucleotidases, Animals, ARL 67156, MLS-0038949, Enzyme Inhibitors, MSCA-1, 5'-Nucleotidase, Evoked Potentials, Cerebral Cortex, CD39, Receptor, Adenosine A1, MLS- 0038949, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Alkaline Phosphatase, Olfactory Bulb, Adenosine Monophosphate, Electric Stimulation, Adenosine A1 Receptor Agonists, Mice, Inbred C57BL, CD73, Female
Abstract: International audience; Extracellular adenosine plays prominent roles in the brain in both physiological and pathological conditions. Adenosine can be generated following the degradation of extracellular nucleotides by various types of ectonucleotidases. Several ectonucleotidases are present in the brain parenchyma: ecto-nucleotide triphosphate diphosphohydrolases 1 and 3 (NTPDase 1 and 3), ecto-nucleotide pyrophosphatase/ phosphodiesterase 1 (NPP 1), ecto-5’-nucleotidase (eN), and tissue non-specific alkaline phosphatase (TNAP, whose function in the brain has received little attention). Here we examined, in a living brain preparation, the role of these ectonucleotidases in generating extracellular adenosine. We recorded local field potentials evoked by electrical stimulation of the lateral olfactory tract in the mouse piriform cortex in vitro. Variations in adenosine level were evaluated by measuring changes in presynaptic inhibition generated by adenosine A1 receptors (A1Rs) activation. A1R-mediated presynaptic inhibition was present endogenously and was enhanced by bath-applied AMP and ATP. We hypothesized that inhibiting ectonucleotidases would reduce extracellular adenosine concentration, which would result in a weakening of presynaptic inhibition. However, inhibiting TNAP had no effect in controlling endogenous adenosine action and no effect on presynaptic inhibition induced by bath-applied AMP. Furthermore, contrary to our expectation, inhibiting TNAP reinforced, rather than reduced, presynaptic inhibition induced by bath-applied ATP. Similarly, inhibition of NTPDase 1 and 3, NPP1, and eN induced stronger, rather than weaker presynaptic inhibition, both in endogenous condition and with bath-applied ATP and AMP. Consequently, attempts to suppress the functions of extracellular adenosine by blocking its extracellular synthesis in living brain tissue could have functional impacts opposite to those anticipated.
Published: 2022

34. Astrocyte‐targeting <scp>RNA</scp> interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Author: Cylia Rochat, Nathalie Bernard‐Marissal, Emma Källstig, Sylvain Pradervand, Florence E. Perrin, Patrick Aebischer, Cédric Raoul, Bernard L. Schneider, Université de Montpellier (UM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Motor Neurons, 0303 health sciences, Superoxide Dismutase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Amyotrophic Lateral Sclerosis, Mice, Transgenic, Disease Models, Animal, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, Superoxide Dismutase-1, 0302 clinical medicine, Neurology, Astrocytes, Animals, RNA Interference, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1
Published: 2022

35. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Author: Ashish Dugar, Eugenio Mercuri, Xiaodong Wang, Volker Straub, Baoguang Han, Daniela Leone, Navid Khan, Dan Wang, Erica Koenig, Laurent Servais, Andreea Mihaela Seferian, Michela Guglieri, Mariacristina Scoto, Francesco Muntoni, University of Oxford, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Liège (CHU-Liège), Université de Liège, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Sarepta Therapeutics, University of Oxford [Oxford], I-Motion Institut [CHU Trousseau], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università cattolica del Sacro Cuore [Roma] (Unicatt), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], and Gestionnaire, Hal Sorbonne Université
Subjects: Duchenne muscular dystrophy, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, Oligonucleotides, Walk Test, golodirsen, Biochemistry, Dystrophin, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, Multicenter trial, Drug Discovery, Genetics, medicine, Clinical endpoint, Humans, education, Molecular Biology, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Exons, medicine.disease, Original Papers, Exon skipping, 3. Good health, Clinical trial, Muscular Dystrophy, Duchenne, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ambulatory, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, business, 030217 neurology & neurosurgery, exon skipping
Abstract: The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P
Published: 2022

36. Defects in Mouse Cortical Glutamate Uptake Can Be Unveiled In Vivo by a Two-in-One Quantitative Microdialysis

Author: Sandrine Parrot, Alex Corscadden, Louison Lallemant, Hélène Benyamine, Jean-Christophe Comte, Aline Huguet-Lachon, Geneviève Gourdon, Mário Gomes-Pereira, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: 0303 health sciences, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cognitive Neuroscience, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, General Medicine, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: International audience; Extracellular glutamate levels are maintained low by efficient transporters, whose dysfunction can cause neuronal hyperexcitability, excitotoxicity, and neurological disease. While many methods estimate glutamate uptake in vitro/ex vivo, a limited number of techniques address glutamate transport in vivo. Here, we used in vivo microdialysis in a two-in-one approach combining reverse dialysis of isotopic glutamate to measure uptake ability and zero-flow (ZF) methods to quantify extracellular glutamate levels. The complementarity of both techniques is discussed on methodological and anatomical basis. We used a transgenic mouse model of human disease, expressing low levels of the EAAT-2/GLT1 glutamate transporter, to validate our approach in a relevant animal model. As expected, isotopic analysis revealed an overall decrease in glutamate uptake, while the ZF method unveiled higher extracellular glutamate levels in these mice. We propose a sensitive and expedite two-in-one microdialysis approach that is sufficiently robust to reveal significant differences in neurotransmitter uptake and extracellular levels through the analysis of a relatively low number of animals.
Published: 2021

37. The 2022 version of the gene table of neuromuscular disorders (nuclear genome)

Author: Enzo Cohen, Gisèle Bonne, François Rivier, Dalil Hamroun, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de la Colombière, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and MORNET, Dominique
Subjects: Cell Nucleus, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Genome, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuromuscular Diseases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology, Practice Guidelines as Topic, Pediatrics, Perinatology and Child Health, Humans, Neurology (clinical), ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract: International audience
Published: 2021

38. Glial Fibrillary Acidic Protein Autoimmunity

Author: Daniela Molinier-Tiganas, Jonathan Biberon, Quentin Bodard, Véronique Rogemond, Anne Ruiz, Bastien Bouldoires, Celine Derollez, Philippe Diraison, Daniela Andriuta, Alberto Vogrig, Amelie Leblanc, Thomas De Broucker, Aditya Ambati, Philippe Kerschen, Géraldine Picard, Thierry Tchoumi, Eve Chanson, Anne-Laure Kaminsky, Irina Grigorashvili-Coin, Clementine Fort, Fanny Duval, Roxana Genet, Jérôme Honnorat, Kumaran Deiva, Sergio Muñiz-Castrillo, Mathilde Goudot, Bastien Joubert, François Sellal, Gabriel Mirebeau, Anais Dutray, Marion Philbert, Guillaume Rieul, Véronique Bourg, Erwan Morvan, Jonathan Ciron, Adrien Bigot, Romain Marignier, Roxana Ameli, Lucie Hopes, Jean Louis Devoize, Nahema Issa, Mickael Bonnan, Elena-Camelia Rusu, Laurent Kremer, Florence Rulquin, Alice Gravier Dumonceau, Marie Benaiteau, 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), Département de Neuroradiologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, CHU Toulouse [Toulouse], Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Excitabilité nerveuse et thérapeutique (ENT), Hôpital Henri Mondor-EA 4391, Service de Physiologie Explorations Fonctionnelles-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpitaux Civils de Colmar, Centre Psychothérapique de Nancy [Laxou] (CPN), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Groupe hospitalier Pellegrin, CHU Bordeaux [Bordeaux], Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Saint Jean de Perpignan, Centre Hospitalier d'Angoulême (CH Angoulême), Université des Antilles - UFR des sciences médicales Hyacinthe Bastaraud (UA UFR SM), Université des Antilles (UA), CHU Clermont-Ferrand, Service de Neurologie [Brest], Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de neurologie [Amiens], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital Pasteur [Nice] (CHU), CHU de Saint-Brieuc, CHU Pau, 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), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Université Grenoble Alpes (UGA), and ANR-18-RHUS-0012,BETPSY,Biomarkers in autoimmune EncephaliTis and Paraneoplastic neurological SYndromes(2018)
Subjects: Adult, Male, Pathology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myelitis, Autoimmunity, Autoimmune Diseases, Cohort Studies, Autoimmune Diseases of the Nervous System, Cerebrospinal fluid, Glial Fibrillary Acidic Protein, medicine, Humans, Child, Autoantibodies, Retrospective Studies, biology, Glial fibrillary acidic protein, business.industry, Autoantibody, Meningoencephalitis, medicine.disease, Hyperintensity, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunohistochemistry, Neurology (clinical), Antibody, business
Abstract: Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.
Published: 2021

39. A medullary centre for lapping in mice

Author: Dempsey, Bowen, Sungeelee, Selvee, Bokiniec, Phillip, Chettouh, Zoubida, Diem, Séverine, Autran, Sandra, Harrell, Evan R., Poulet, James F. A., Birchmeier, Carmen, Carey, Harry, Genovesio, Auguste, McMullan, Simon, Goridis, Christo, Fortin, Gilles, Brunet, Jean-François, Fortin, Gilles, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), 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)-École normale supérieure - Paris (ENS-PSL), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Macquarie University [Sydney], ANR-17-CE16-0006,HEARTBRAIN,Développement et Physiologie des Neurones Intrinsèques du Cœur(2017), ANR-19-CE16-0029,HOMORESP,Résaux neuronaux homotypiques du contrôle respiratoire(2019), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS 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)-École normale supérieure - Paris (ENS 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), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Macquarie University, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Science, Action Potentials, Neural circuits, behavioral disciplines and activities, Article, Mice, Tongue, Animals, Central pattern generators, Homeodomain Proteins, Mice, Knockout, Motor Neurons, Medulla Oblongata, Reticular Formation, digestive, oral, and skin physiology, fungi, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, food and beverages, Feeding Behavior, Jaw, Female, Function and Dysfunction of the Nervous System, Brain Stem, Transcription Factors
Abstract: It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mice. These neuronal groups, IRtPhox2b and Peri5Atoh1, are marked by expression of the pan-autonomic homeobox gene Phox2b and are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the subcortical nuclei underpinning a stereotyped feeding behavior., Orofacial movements for feeding can be triggered, coordinated and rhythmically organised at the level of the brainstem. Here, the authors show two nuclei can organise the stereotyped movements for ingesting fluids in mammals, these neuronal groups are marked by expression of Phox2b and are located in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve.
Published: 2021

40. Polyglutamine-expanded ATXN7 alters a specific epigenetic signature underlying photoreceptor identity gene expression in SCA7 mouse retinopathy

Author: Anna Niewiadomska-Cimicka, Antoine Hache, Stéphanie Le Gras, Céline Keime, Tao Ye, Aurelie Eisenmann, Imen Harichane, Michel J. Roux, Nadia Messaddeq, Emmanuelle Clérin, Thierry Léveillard, Yvon Trottier, 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), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE12-0026,SAGA-Retina,Rôle du complexe co-activateur SAGA dans la transcription au cours de la différenciation cellulaire chez les mammifères(2018), ANR-15-JPWG-0008,ModelPolyQ,Advanced models of polyglutamine disorders -HD, SCA2, SCA3, SCA7-(2015), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), and European Project: 643417,H2020,H2020-HCO-2014,JPco-fuND(2015)
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Pharmacology (medical), Cell Biology, General Medicine, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Molecular Biology
Abstract: Background Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder that primarily affects the cerebellum and retina. SCA7 is caused by a polyglutamine expansion in the ATXN7 protein, a subunit of the transcriptional coactivator SAGA that acetylates histone H3 to deposit narrow H3K9ac mark at DNA regulatory elements of active genes. Defective histone acetylation has been presented as a possible cause for gene deregulation in SCA7 mouse models. However, the topography of acetylation defects at the whole genome level and its relationship to changes in gene expression remain to be determined. Methods We performed deep RNA-sequencing and chromatin immunoprecipitation coupled to high-throughput sequencing to examine the genome-wide correlation between gene deregulation and alteration of the active transcription marks, e.g. SAGA-related H3K9ac, CBP-related H3K27ac and RNA polymerase II (RNAPII), in a SCA7 mouse retinopathy model. Results Our analyses revealed that active transcription marks are reduced at most gene promoters in SCA7 retina, while a limited number of genes show changes in expression. We found that SCA7 retinopathy is caused by preferential downregulation of hundreds of highly expressed genes that define morphological and physiological identities of mature photoreceptors. We further uncovered that these photoreceptor genes harbor unusually broad H3K9ac profiles spanning the entire gene bodies and have a low RNAPII pausing. This broad H3K9ac signature co-occurs with other features that delineate superenhancers, including broad H3K27ac, binding sites for photoreceptor specific transcription factors and expression of enhancer-related non-coding RNAs (eRNAs). In SCA7 retina, downregulated photoreceptor genes show decreased H3K9 and H3K27 acetylation and eRNA expression as well as increased RNAPII pausing, suggesting that superenhancer-related features are altered. Conclusions Our study thus provides evidence that distinctive epigenetic configurations underlying high expression of cell-type specific genes are preferentially impaired in SCA7, resulting in a defect in the maintenance of identity features of mature photoreceptors. Our results also suggest that continuous SAGA-driven acetylation plays a role in preserving post-mitotic neuronal identity.
Published: 2022

41. Développement de techniques CEST à ultra-haut champ pour l'étude du métabolisme cérébral

Author: Bardin, Solène, Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB), 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)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Luisa Ciobanu, and Fawzi Boumezbeur
Subjects: Ultra-High field, Ultra-Haut champ, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Métabolisme cérébral, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Cerebral metabolism, IRM fonctionnelle, CEST, MRI, Functional MRI, IRM
Abstract: Chemical exchange saturation transfer Magnetic Resonance Imaging (CEST MRI) is a powerful tool for metabolic imaging. Detection of specific neurometabolites can be performed using CEST MRI with enhanced sensitivity, and temporal and spatial resolution compared to NMR Spectroscopy (MRS), by measuring the reduction in bulk water signal after application of a dedicated presaturation module. With the increased availability of high and ultra-high magnetic fields, CEST MRI techniques gained a lot of attention. Significant advancements have been reported in both the acquisition strategies and processing pipelines which allowed the in vivo detection of numerous brain metabolites including glutamate, glucose, myo-inositol, lactate, creatine and promising applications in different disciplines (e.g. oncology, musculoskeletal sciences, physiology or neurosciences) have been demonstrated. Yet, it remains challenging to investigate weaker CEST effects from molecules with lower concentrations or slower exchange rates or detect rapid CEST changes. This PhD thesis aimed at the development of ultra-high field CEST technics for studying brain metabolism in vivo. In this project, the advantage of ultra-high magnetic fields for CEST imaging was first demonstrated in vitro through an investigation of the CEST detection of three major neurometabolites: glucose, lactate and glutamate at different high magnetic fields (9.4, 11.7 and 17.2 T). The influence of temperature and pH changes on the CEST response was also investigated. In the second part of this thesis, the development and implementation of a new ultrafast CEST MRI approach are presented: the “CEST-linescan” sequence. This method is adapted to the detection of the tenuous CEST effects generated by metabolites with very low concentrations and very low exchange rates. Due to its rapidity, this acquisition protocol is offering a better signal stability while maintaining a contrast-to-noise ratio similar to that of standard CEST sequences. For processing, we used an analysis tool (PEAKIT) developed in our team specifically for characterizing CEST contributions. PEAKIT estimates the CEST peak height, area and statistical significance based on the estimation of the local baseline around the CEST contribution-of-interest and is therefore minimally impacted by the global shape of the CEST data. These two CEST-related tools enabled, for the first time, the in vivo detection (in the skeletal muscle and in the brain of rats) of carnosine, an endogenous dipeptide with important antioxidant functions known to be involved notably in the cellular response to high levels of inflammation. Two other derivatives of carnosine (anserine and homocarnosine) were also studied. In the last part of the project, we focused on adapting the ultrafast CEST-linescan sequence for the investigation of dynamic metabolic changes in the rat brain. A preliminary study consisted in detecting changes in the CEST contrast induced by a controlled pH decrease. We were then focused on monitoring metabolic changes induced by neuronal activation triggered by an electrical forepaw stimulation in rats. We made several sequence modifications and implemented various acquisition strategies in order to minimize the BOLD effects and maintain the sensitivity and (biochemical) specificity of the CEST signal changes. Even though the results obtained did not allow us to detect significant changes in specific CEST contributions during the functional task, we conclude that the imaging protocols developed are promising. By employing stimulation paradigms optimized for stable activation responses and increasing the number of animals for higher statistical power, we expect to be able to pinpoint transient metabolic changes driven by neuronal activity.; L'imagerie RMN de transfert de saturation par échange chimique (IRM CEST) est un outil puissant pour l'imagerie métabolique. L'IRM CEST permet de détecter indirectement des métabolites avec une sensibilité et des résolutions temporelle et spatiale accrues par rapport à la spectroscopie RMN (SRM), via la réduction du signal de l'eau après l'application d'un module de présaturation à la fréquence du métabolite. Grâce à l'avènement des champs magnétiques intenses pour l'IRM, l'IRM CEST suscite un intérêt croissant. Des avancées significatives ont été rapportées aussi bien dans les stratégies d'acquisition que les chaînes de traitement permettant la détection de nombreux métabolites dont le glucose, le glutamate, le myo-inositol, le lactate ou la créatine, et des applications prometteuses dans différentes disciplines (oncologie, sciences musculo-squelettiques, physiologie ou neurosciences) ont été proposées. Cependant, il reste difficile d'étudier les effets CEST plus faibles provenant de métabolites moins concentrés, en échange lent ou de détecter des changements CEST rapides. Cette thèse de doctorat visait à développer des techniques CEST à ultra-haut champ pour étudier le métabolisme cérébral in vivo. D'abord, l'avantage des ultra-hauts champs magnétiques pour l'imagerie CEST a été démontré in vitro par l'étude de trois neurométabolites majeurs : glucose, lactate et glutamate à différents champs magnétiques (9.4, 11.7 et 17.2 T). L'influence des changements de température et de pH sur la réponse CEST a également été étudiée. Puis, le développement et l'implémentation d'une nouvelle approche d'IRM CEST ultra-rapide sont présentés : la séquence " CEST-linescan ". Cette méthode est adaptée à la détection des effets CEST ténus générés par des métabolites moins concentrés ou en échange lent. Grâce à sa rapidité, ce protocole d'acquisition offre une meilleure stabilité du signal tout en maintenant un rapport contraste/bruit similaire aux séquences CEST standards. Pour le traitement des données, un outil d'analyse (PEAKIT) spécifiquement dédié à la caractérisation de contributions CEST a été développé au sein de notre équipe. PEAKIT estime la hauteur, la surface et la significativité statistique du pic CEST en se basant sur l'estimation de la ligne de base locale autour de la contribution CEST d'intérêt et est donc peu affecté par la forme globale des données CEST. Ces deux outils dédiés ont permis, pour la première fois, la détection in vivo (dans le muscle squelettique et dans le cerveau du rat) de la carnosine, un dipeptide endogène doté d'importantes fonctions antioxydantes et connu pour être impliqué notamment dans la réponse cellulaire à des niveaux élevés d'inflammation. Deux autres dérivés de la carnosine (anserine et homocarnosine) ont également été étudiés. Enfin, nous avons adapté le CEST-linescan ultrarapide afin d'étudier les changements métaboliques dynamiques dans le cerveau du rat. Une étude préliminaire a consisté à détecter les changements du contraste CEST induits par une variation contrôlée du pH. Nous avons ensuite étudié les changements métaboliques induits par l'activation neuronale déclenchée par une stimulation électrique de la patte avant chez le rat. Nous avons adapté la séquence et mis en œuvre diverses stratégies d'acquisition afin de minimiser les effets BOLD et maintenir la sensibilité et la spécificité (biochimique) du contraste CEST fonctionnel. Même si les résultats obtenus ne nous ont pas permis de détecter des changements significatifs dans les contributions CEST spécifiques pendant la tâche fonctionnelle, nous concluons que les protocoles d'imagerie développés demeurent prometteurs. En employant des paradigmes de stimulation optimisés pour des réponses d'activation plus stables et en augmentant le nombre d'animaux pour une plus grande puissance statistique, nous espérons être en mesure d'identifier les changements métaboliques transitoires induits par l'activité neuronale.
Published: 2022

42. Aryl hydrocarbon receptors are involved in the pathogenesis of migraine

Author: Mrad, Yara, Neuro-Dol (Neuro-Dol), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Abstract: International audience
Published: 2022

43. Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity

Author: Raphaël Dos Reis, Etienne Kornobis, Alyssa Pereira, Frederic Tores, Judit Carrasco, Candice Gautier, Céline Jahannault-Talignani, Patrick Nitschké, Christian Muchardt, Andreas Schlosser, Hans Michael Maric, Fabrice Ango, Eric Allemand, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Régulation épigénétique - Epigenetic regulation, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, University of Würzburg = Universität Würzburg, This study was supported by: - The Deutsche Forschungsgemeinschaft (DFG MA6957/1-1), M.M.H. - The ERANet NEURON/DECODE (18-NEUR-0004), F.A. - The REVIVE funding from ANR 'Laboratoire d’Excellence' (2011–2021), C.M and E.A. - The ANR KREM-AIF (ANR-21-CE17-0014-02), E.A., We thank Y. Lallemand and Y. Porozhan for their help in perfusing mouse for ribosomal fractionation, the iExplore and RIO-Imaging Platforms of Montpellier for their support, CSHL PacBio sequencing platform. We thank A.R. Krainer, M.L. Hastings, S. Dokudovskaya, O. Mauger, E. Batsché, O. Espeli, and P. Carroll for the critical reading of the manuscript. We thank L. Telley for his initial contribution to PACBIO analysis., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-21-CE17-0014,KREM-AIF,KREMEN2, un nouvel inhibiteur de l'auto-inflammation médié par NF-kB impliqué dans les maladies généiques humaines(2021), Ango, Fabrice, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, and KREMEN2, un nouvel inhibiteur de l'auto-inflammation médié par NF-kB impliqué dans les maladies généiques humaines - - KREM-AIF2021 - ANR-21-CE17-0014 - AAPG2021 - VALID
Subjects: Proteomics, Multidisciplinary, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Membrane Proteins, General Physics and Astronomy, General Chemistry, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Receptors, GABA-A, General Biochemistry, Genetics and Molecular Biology, Receptors, GABA, Synapses, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Protein Isoforms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Carrier Proteins
Abstract: Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and gamma-aminobutyric acid A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.
Published: 2022

44. The recurrent TCF4 missense variant p.( Arg389Cys ) causes a neurodevelopmental disorder overlapping with but not typical for Pitt‐Hopkins syndrome

Author: Bernt, Popp, Thierry, Bienvenu, Irina, Giurgea, Julia, Metreau, Cornelia, Kraus, André, Reis, Jan, Fischer, María Palomares, Bralo, Jair, Tenorio-Castaño, Pablo, Lapunzina, Berta, Almoguera, Fermina, Lopez-Grondona, Heinrich, Sticht, Christiane, Zweier, Universität Leipzig [Leipzig], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Hospital Universitario La Paz, Centro Nacional de Microbiología [ISCIII, Madrid, Spain] (CNM), Instituto de Salud Carlos III [Madrid] (ISC), Inselspital Bern, Universität Bern [Bern] (UNIBE), and Couvet, Sandrine
Subjects: Epilepsy, MESH: Humans, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Facies, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, missense variant, neurodevelopmental disorder, PTHS, MESH: Intellectual Disability, MESH: Hyperventilation, [SDV] Life Sciences [q-bio], Transcription Factor 4, MESH: Facies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Pitt-Hopkins syndrome, MESH: Epilepsy, Humans, Hyperventilation, MESH: Transcription Factor 4, TCF4
Abstract: International audience; TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non-specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator-recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype-phenotype correlation for TCF4-related NDDs.
Published: 2022

45. Ultrasound localization microscopy and functional ultrasound imaging reveal atypical features of the trigeminal ganglion vasculature

Author: Annabelle Réaux-Le-Goazigo, Benoit Beliard, Lauriane Delay, Line Rahal, Julien Claron, Noémi Renaudin, Isabelle Rivals, Miguel Thibaut, Mohamed Nouhoum, Thomas Deffieux, Mickael Tanter, Sophie Pezet, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physique pour la médecine (PhysMed Paris), 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), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Paris sciences et lettres (PSL), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Lille, Iconeus, Physique des ondes pour la médecine, Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), 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), Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE37-0005,PINCH,Altérations de la connectivité cérébrale associée à la douleur persistante(2018), and ANR-21-CE16-0018,CONNECTPAIN,Influence de la microglie sur les voies nerveuses de la douleur neuropathique cornéenne(2021)
Subjects: Rats, Sprague-Dawley, Microscopy, [SPI]Engineering Sciences [physics], Trigeminal Ganglion, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Face, Medicine (miscellaneous), Animals, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology, Rats, Ultrasonography
Abstract: The functional imaging within the trigeminal ganglion (TG) is highly challenging due to its small size and deep localization. This study combined a methodological framework able to dive into the rat trigeminal nociceptive system by jointly providing 1) imaging of the TG blood vasculature at microscopic resolution, and 2) the measurement of hemodynamic responses evoked by orofacial stimulations in anesthetized rats. Despite the small number of sensory neurons within the TG, functional ultrasound imaging was able to image and quantify a strong and highly localized hemodynamic response in the ipsilateral TG, evoked not only by mechanical or chemical stimulations of corneal nociceptive fibers, but also by cutaneous mechanical stimulations of the ophthalmic and maxillary orofacial regions using a von Frey hair. The in vivo quantitative imaging of the TG’s vasculature using ultrasound localization microscopy combined with in toto labelling reveals particular features of the vascularization of the area containing the sensory neurons, that are likely the origin of this strong vaso-trigeminal response. This innovative imaging approach opens the path for future studies on the mechanisms underlying changes in trigeminal local blood flow and evoked hemodynamic responses, key mechanisms for the understanding and treatment of debilitating trigeminal pain conditions.
Published: 2022

46. Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development

Author: Vincent Dupuy, Matthieu Prieur, Anne Pizzoccaro, Clara Margarido, Emmanuel Valjent, Joël Bockaert, Tristan Bouschet, Philippe Marin, Séverine Chaumont-Dubel, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), ANR-17-CE16-0010,Sero6Dev,Réseau de signalisation associé au récepteur 5-HT6 et développement neuronal(2017), ANR-16-IDEX-0006,MUSE,MUSE(2016), Guerineau, Nathalie C., Réseau de signalisation associé au récepteur 5-HT6 et développement neuronal - - Sero6Dev2017 - ANR-17-CE16-0010 - AAPG2017 - VALID, and MUSE - - MUSE2016 - ANR-16-IDEX-0006 - IDEX - VALID
Subjects: [SDV] Life Sciences [q-bio], Primary cilium, Neurology, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuronal development, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Serotonin receptor
Abstract: International audience; The serotonin 5-HT6 receptor (5-HT6R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin.
Published: 2022

47. Chemogenetic stimulation of adult neurogenesis, and not neonatal neurogenesis, is sufficient to improve long-term memory accuracy

Author: Marie Lods, Pierre Mortessagne, Emilie Pacary, Geoffrey Terral, Fanny Farrugia, Wilfrid Mazier, Nuria Masachs, Vanessa Charrier, Daniela Cota, Guillaume Ferreira, Djoher Nora Abrous, Sophie Tronel, Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et Neurobiologie intégrée (NutriNeuro), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and tronel, sophie
Subjects: History, Memory, Long-Term, Polymers and Plastics, General Neuroscience, Neurogenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Adult neurogenesis, Hippocampus, Industrial and Manufacturing Engineering, Rats, Chemogenetic, Memory, Animals, Learning, Business and International Management
Abstract: International audience; Hippocampal adult neurogenesis is involved in many memory processes from learning, to remembering and forgetting. However, whether or not the stimulation of adult neurogenesis is a sufficient condition to improve memory performance remains unclear. Here, we developed and validated, using ex-vivo electrophysiology, a chemogenetic approach that combines selective tagging and activation of discrete adult-born neuron populations. Then we demonstrated that, in rats, this activation can improve accuracy and strength of remote memory. These results show that stimulation of adult-born neuron activity can counteract the natural fading of memory traces that occurs with the passage of time. This opens up new avenues for treating memory problems that may arise over time.
Published: 2022

48. Genome-wide analysis of genes encoding core components of the ubiquitin system during cerebral cortex development

Author: Alexandre Bouron, Marie-Odile Fauvarque, Genetics and Chemogenomics (GenChem ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), 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)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Cerebral Cortex, Cellular and Molecular Neuroscience, Ubiquitin, Ubiquitin-Protein Ligases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ubiquitination, Proteins, Molecular Biology
Abstract: Ubiquitination involves three types of enzymes (E1, E2, E3) acting sequentially to attach ubiquitin (Ub) to target proteins. This post-translational modification controls key cellular processes like the degradation of proteins, endocytosis, subcellular localization and activity of proteins. The ubiquitination, which can be reversed by deubiquitinating enzymes (DUBs), plays important roles during brain development. Furthermore, deregulation of the Ub system is linked to the pathogenesis of various diseases including neurodegenerative disorders. We have used a publicly available RNAseq database to conduct an extensive genome-wide gene expression analysis of the core components of the Ub machinery, covering Ub genes as well as E1, E2, E3 and DUB genes. The ubiquitination network was merely governed by Uba1 and Ube2m, the predominant E1 and E2 genes, respectively. There expression was positively regulated during cortical formation. The principal genes coding for HECT (homologous to the E6-AP carboxyl terminus), RBR (RING-in-between-RING), and RING (really interesting new gene) E3 Ub ligases were also prominently regulated. Pja1, Dtx3 (RING ligases) and Stub1 (U-box RING) were the most highly expressed E3 Ub ligase genes and displayed distinct developmental expression patterns. Moreover, > 80 DUB genes were expressed during corticogenesis with two prominent actors Uch-l1 and Usp22 that were strongly up-regulated. Several components of the Ub system overexpressed in cancers were highly expressed in the cerebral cortex under conditions not related to tumour formation or progression. Altogether, this work provides an in-depth overview of the transcriptomic changes during the embryonic formation of the cerebral cortex. The data also offer new insight for the characterization of the Ub system and may contribute to a better understanding of its involvement in the pathogenesis of neurodevelopmental disorders.
Published: 2022

49. Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Author: van Cruchten, Remco, van As, Daniël, Glennon, Jeffrey, van Engelen, Baziel, Okkersen, K, Jimenez-Moreno, C, Wenninger, S, Daidj, F, Cumming, S, Littleford, R, Monckton, D, Lochmüller, H, Catt, M, Faber, C, Hapca, A, Donnan, P, Gorman, G, Bassez, G, Schoser, B, Knoop, H, Treweek, S, Wansink, Derick, Impens, Francis, Gabriels, Ralf, Claeys, Tine, Ravel-Chapuis, Aymeric, Jasmin, Bernard, Mahon, Niamh, Nieuwenhuis, Sylvia, Martens, Lennart, Novak, Petr, Furling, Denis, Baak, Arie, Gourdon, Genevieve, Mackenzie, Alex, Martinat, Cecile, Neault, Nafisa, Roos, Andreas, Duchesne, Elise, Salz, Renee, Thompson, Rachel, Baghdoyan, Sandrine, Varghese, Anu, Blom, Paul, Spendiff, Sally, Manta, Alexander, Medical Psychology, APH - Mental Health, Radboud University Medical Center [Nijmegen], University College Dublin [Dublin] (UCD), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Newcastle University [Newcastle], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Lifestyle intervention, Myotonic dystrophy type 1, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Therapeutic Response, Gene Expression, Peripheral blood, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Nerve Tissue Proteins, General Medicine, Biomarker, HSP40 Heat-Shock Proteins, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], All institutes and research themes of the Radboud University Medical Center, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Myotonic Dystrophy, RNA, Messenger, RNA-seq, Carrier Proteins, Trinucleotide Repeat Expansion, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract: Background Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.
Published: 2022

50. Age-dependent meningeal macrophages protect against viral neuroinfection

Author: Rebejac, Julie, Eme-Scolan, Elisa, Teleman, Matei, Spinelli, Lionel, Gallo, Emeline, Roussel-Queval, Annie, Zarubica, Ana, Malissen, Bernard, Michallet, Marie-Cécile, Lawrence, Toby, Manglani, Monica, McGavern, Dorian, Rua, Rejane, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunophénomique (CIPHE), Xinxiang Medical University, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), King‘s College London, and National Institutes of Health [Bethesda] (NIH)
Subjects: Meninges, Immunological barrier, Macrophages, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Interferon, Neuroinfection, LCMV, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Virus
Abstract: International audience; Due to the vital importance of the Central Nervous System (CNS), its potential infection and inflammation have to be tightly controlled. The surface of the CNS is connected to the periphery by a rich and complex tissue, the meninges. They contain a vast network of macrophages subdivided in at least two subpopulations endowed with elusive functions: a neonatal, MHC-II negative macrophage population, and an age-dependent population expressing MHC-II. Using in situ-histocytometry, flow cytometry, and single-cell RNA sequencing approaches, we showed that those populations have opposite dynamic behaviors in response to in vivo peripheral challenges such as LPS, SARS-CoV2 and lymphocytic choriomeningitis virus (LCMV), with an apparent contraction of the MHC-II+ population. Focusing on LCMV infection in experimental mouse models and using innovative pharmacological and genetic depletion strategies, we show that meningeal macrophages (MM) represent an early line of protection against this neuroinvasive pathogen. In their absence, specific areas in the meninges became highly infected, leading to fatal brain disease. While their intrinsic sensing of viral replication through the Mitochondrial antiviral-signaling protein (MAVS) was dispensable, sensing of IFNs through the STAT1 pathway played an important role in controlling viral spread. Unexpectedly, the age-dependent MHC-II+ macrophage population had an important role in controlling neuroinfection, by shutting down biosynthesis pathways and efficiently blocking viral replication. This work helps understanding the spatial organization of the brain defense system and the cellular and molecular mechanisms involved in CNS protection.
Published: 2022

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