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1. CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway

Author

Benoît Boulan, Charlotte Ravanello, Amandine Peyrel, Christophe Bosc, Christian Delphin, Florence Appaix, Eric Denarier, Alexandra Kraut, Muriel Jacquier-Sarlin, Alyson Fournier, Annie Andrieux, Sylvie Gory-Fauré, and Jean-Christophe Deloulme

Subjects
CRMP4, fornix, axonal guidance, Semaphorin-3E, detergent-resistant membrane domains, lipid rafts, Medicine, Science, Biology (General), QH301-705.5
Abstract

Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular effectors transduce axonal guidance signals by remodeling the cytoskeleton. Semaphorin-3E (Sema3E) is a guidance cue implicated in development of the fornix, a neuronal tract connecting the hippocampus to the hypothalamus. Microtubule-associated protein 6 (MAP6) has been shown to be involved in the Sema3E growth-promoting signaling pathway. In this study, we identified the collapsin response mediator protein 4 (CRMP4) as a MAP6 partner and a crucial effector in Sema3E growth-promoting activity. CRMP4-KO mice displayed abnormal fornix development reminiscent of that observed in Sema3E-KO mice. CRMP4 was shown to interact with the Sema3E tripartite receptor complex within detergent-resistant membrane (DRM) domains, and DRM domain integrity was required to transduce Sema3E signaling through the Akt/GSK3 pathway. Finally, we showed that the cytoskeleton-binding domain of CRMP4 is required for Sema3E’s growth-promoting activity, suggesting that CRMP4 plays a role at the interface between Sema3E receptors, located in DRM domains, and the cytoskeleton network. As the fornix is affected in many psychiatric diseases, such as schizophrenia, our results provide new insights to better understand the neurodevelopmental components of these diseases.

Published
2021
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2. Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories

Author

Camille Cuveillier, Benoit Boulan, Charlotte Ravanello, Eric Denarier, Jean-Christophe Deloulme, Sylvie Gory-Fauré, Christian Delphin, Christophe Bosc, Isabelle Arnal, and Annie Andrieux

Subjects
microtubule, microtubule-associated-proteins, actin, neuron, synapse, psychiatric disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.

Published
2021
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3. Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia

Author

Sylvie Gory-Fauré, Rebecca Powell, Julie Jonckheere, Fabien Lanté, Eric Denarier, Leticia Peris, Chi Hung Nguyen, Alain Buisson, Laurence Lafanechère, and Annie Andrieux

Subjects
MAP6, LIM kinase, actin, microtubule, therapeutics, cytoskeleton, Therapeutics. Pharmacology, RM1-950
Abstract

The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.

Published
2021
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4. AutoNeuriteJ: An ImageJ plugin for measurement and classification of neuritic extensions.

Author

Benoit Boulan, Anne Beghin, Charlotte Ravanello, Jean-Christophe Deloulme, Sylvie Gory-Fauré, Annie Andrieux, Jacques Brocard, and Eric Denarier

Subjects
Medicine, Science
Abstract

Morphometry characterization is an important procedure in describing neuronal cultures and identifying phenotypic differences. This task usually requires labor-intensive measurements and the classification of numerous neurites from large numbers of neurons in culture. To automate these measurements, we wrote AutoNeuriteJ, an imageJ/Fiji plugin that measures and classifies neurites from a very large number of neurons. We showed that AutoNeuriteJ is able to detect variations of neuritic growth induced by several compounds known to affect the neuronal growth. In these experiments measurement of more than 5000 mouse neurons per conditions was obtained within a few hours. Moreover, by analyzing mouse neurons deficient for the microtubule associated protein 6 (MAP6) and wild type neurons we illustrate that AutoNeuriteJ is capable to detect subtle phenotypic difference in axonal length. Overall the use of AutoNeuriteJ will provide rapid, unbiased and accurate measurement of neuron morphologies.

Published
2020
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5. A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines

Author

Leticia Peris, Mariano Bisbal, José Martinez-Hernandez, Yasmina Saoudi, Julie Jonckheere, Marta Rolland, Muriel Sebastien, Jacques Brocard, Eric Denarier, Christophe Bosc, Christophe Guerin, Sylvie Gory-Fauré, Jean Christophe Deloulme, Fabien Lanté, Isabelle Arnal, Alain Buisson, Yves Goldberg, Laurent Blanchoin, Christian Delphin, and Annie Andrieux

Subjects
Science
Abstract

Microtubule-associated protein 6 (MAP6) is known to be important for synaptic plasticity and cognition, supposedly via interaction with microtubules. Here, the authors found that MAP6 is crucial for the stabilisation of enlarged synapses through its association with a different cytoskeletal element, actin.

Published
2018
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6. Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction

Author

Muriel Sébastien, Benoit Giannesini, Perrine Aubin, Julie Brocard, Mathilde Chivet, Laura Pietrangelo, Simona Boncompagni, Christophe Bosc, Jacques Brocard, John Rendu, Sylvie Gory-Fauré, Annie Andrieux, Anne Fourest-Lieuvin, Julien Fauré, and Isabelle Marty

Subjects
Microtubule-associated protein, Muscle contraction, Calcium release, Microtubules, Sarcoplasmic reticulum, Triad, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background The skeletal muscle fiber has a specific and precise intracellular organization which is at the basis of an efficient muscle contraction. Microtubules are long known to play a major role in the function and organization of many cells, but in skeletal muscle, the contribution of the microtubule cytoskeleton to the efficiency of contraction has only recently been studied. The microtubule network is dynamic and is regulated by many microtubule-associated proteins (MAPs). In the present study, the role of the MAP6 protein in skeletal muscle organization and function has been studied using the MAP6 knockout mouse line. Methods The presence of MAP6 transcripts and proteins was shown in mouse muscle homogenates and primary culture using RT-PCR and western blot. The in vivo evaluation of muscle force of MAP6 knockout (KO) mice was performed on anesthetized animals using electrostimulation coupled to mechanical measurement and multimodal magnetic resonance. The impact of MAP6 deletion on microtubule organization and intracellular structures was studied using immunofluorescent labeling and electron microscopy, and on calcium release for muscle contraction using Fluo-4 calcium imaging on cultured myotubes. Statistical analysis was performed using Student’s t test or the Mann-Whitney test. Results We demonstrate the presence of MAP6 transcripts and proteins in skeletal muscle. Deletion of MAP6 results in a large number of muscle modifications: muscle weakness associated with slight muscle atrophy, alterations of microtubule network and sarcoplasmic reticulum organization, and reduction in calcium release. Conclusion Altogether, our results demonstrate that MAP6 is involved in skeletal muscle function. Its deletion results in alterations in skeletal muscle contraction which contribute to the global deleterious phenotype of the MAP6 KO mice. As MAP6 KO mouse line is a model for schizophrenia, our work points to a possible muscle weakness associated to some forms of schizophrenia.

Published
2018
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7. Cryo-EM Visualization of Neuronal Particles Inside Microtubules

Author

Sylvie, Gory-Fauré, Julie, Delaroche, Camille, Cuveillier, Christian, Delphin, and Isabelle, Arnal

Subjects
Neurons, Mice, Cryoelectron Microscopy, Animals, Hippocampus, Microtubules
Abstract

Neuronal microtubules have long been known to contain intraluminal particles, called MIPs (microtubule inner proteins), most likely involved in the extreme stability of microtubules in neurons. This chapter describes a cryo-electron microscopy-based assay to visualize microtubules containing neuronal MIPs. We present two protocols to prepare MIPs-containing microtubules, using either in vitro microtubule polymerization assays or extraction of microtubules from mouse hippocampal neurons in culture.

Published
2022

8. Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease

Author

Leticia Peris, Julie Parato, Xiaoyi Qu, Jean Marc Soleilhac, Fabien Lanté, Atul Kumar, Maria Elena Pero, José Martínez-Hernández, Charlotte Corrao, Giulia Falivelli, Floriane Payet, Sylvie Gory-Fauré, Christophe Bosc, Marian Blanca Ramirez, Andrew Sproul, Jacques Brocard, Benjamin Di Cara, Philippe Delagrange, Alain Buisson, Yves Goldberg, Marie Jo Moutin, Francesca Bartolini, Annie Andrieux, Peris, Leticia, Parato, Julie, Qu, Xiaoyi, Soleilhac, Jean-Marc, Lanté, Fabien, Kumar, Atul, Pero, Maria Elena, Martínez-Hernández, José, Corrao, Charlotte, Falivelli, Giulia, Payet, Floriane, Gory-Fauré, Sylvie, Bosc, Christophe, Blanca Ramírez, Marian, Sproul, Andrew, Brocard, Jacque, Di Cara, Benjamin, Delagrange, Philippe, Buisson, Alain, Goldberg, Yve, Moutin, Marie-Jo, Bartolini, Francesca, and Andrieux, Annie

Subjects
dendritic spine, macromolecular substances, Microtubules, neuron, Mice, tubulin, Alzheimer Disease, Animals, Humans, Tyrosine, Neurology (clinical), Peptides, Alzheimer’s disease, microtubule
Abstract

Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions that go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase (TTL). Here we show that TTL heterozygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density and both synaptic plasticity and memory deficits. We further report decreased TTL expression in sporadic and familial Alzheimer’s disease, and reduced microtubule dynamics in human neurons harbouring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid-β peptide toxicity and that expression of TTL, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid-β peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid-β peptide-induced synaptic damage and that this balance is lost in Alzheimer’s disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer’s disease.

Published
2022

10. CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway

Author

Amandine Peyrel, Jean-Christophe Deloulme, Charlotte Ravanello, Christian Delphin, Alyson E. Fournier, Florence Appaix, Christophe Bosc, Muriel Jaquier-Sarlin, Alexandra Kraut, Sylvie Gory-Fauré, Eric Denarier, Benoit Boulan, Annie Andrieux, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), BioSanté (UMR BioSanté), 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), McGill University = Université McGill [Montréal, Canada], and Bruley, Christophe

Subjects
Male, Receptor complex, Collapsin-Response-Mediator-Proteins, detergent-resistant membrane domains, QH301-705.5, [SDV]Life Sciences [q-bio], Science, Fornix, Brain, Nerve Tissue Proteins, Semaphorins, fornix, Biology, General Biochemistry, Genetics and Molecular Biology, Mice, Mediator, Semaphorin, Animals, MAP6, Biology (General), Growth cone, Protein kinase B, axonal guidance, lipid rafts, General Immunology and Microbiology, General Neuroscience, Fornix, General Medicine, [SDV] Life Sciences [q-bio], nervous system, Semaphorin-3E, Detergent-Resistant-Membrane-Domains, Medicine, Female, Signal transduction, Neuroscience, CRMP4, Research Article, Developmental Biology, Signal Transduction
Abstract

Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular effectors transduce axonal guidance signals by remodeling the cytoskeleton. Semaphorin-3E (Sema3E) is a guidance cue implicated in development of the fornix, a neuronal tract connecting the hippocampus to the hypothalamus. Microtubule-associated protein 6 (MAP6) has been shown to be involved in the Sema3E growth-promoting signaling pathway. In this study, we identified the collapsin response mediator protein 4 (CRMP4) as a MAP6 partner and a crucial effector in Sema3E growth-promoting activity. CRMP4-KO mice displayed abnormal fornix development reminiscent of that observed in Sema3E-KO mice. CRMP4 was shown to interact with the Sema3E tripartite receptor complex within detergent-resistant membrane (DRM) domains, and DRM domain integrity was required to transduce Sema3E signaling through the Akt/GSK3 pathway. Finally, we showed that the cytoskeleton-binding domain of CRMP4 is required for Sema3E’s growth-promoting activity, suggesting that CRMP4 plays a role at the interface between Sema3E receptors, located in DRM domains, and the cytoskeleton network. As the fornix is affected in many psychiatric diseases, such as schizophrenia, our results provide new insights to better understand the neurodevelopmental components of these diseases.

Published
2021
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11. Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease

Author

Soleilhac J, Maria Elena Pero, Annie Andrieux, Julie Brocard, Francesca Bartolini, Sylvie Gory-Fauré, Di Cara B, Payet F, Parato J, Marie-Jo Moutin, Qu X, Atul Kumar, Christophe Bosc, Delagrange P, Charlotte Corrao, Leticia Peris, Yves Goldberg, Blanca Ramírez M, Falivelli G, José L. Martínez-Hernández, Fabien Lanté, Alain Buisson, Andrew Sproul, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Columbia University Medical Center (CUMC), Columbia University [New York], University of Naples Federico II, Institut de Recherches SERVIER (IRS), University of Naples Federico II = Università degli studi di Napoli Federico II, and Moutin, Marie-Jo

Subjects
0303 health sciences, biology, Chemistry, [SDV]Life Sciences [q-bio], Neurodegeneration, Neurotransmission, medicine.disease, Cell biology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Tubulin, Microtubule, Detyrosination, Synaptic plasticity, medicine, biology.protein, Spine injury, Tyrosine, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SUMMARYIn neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of α-tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL+/− mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimer’s disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Amyloidβ1-42 and that TTL, by promoting microtubule entry into spines, prevents Aβ1-42-induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

Published
2021

13. Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia

Author

Sylvie, Gory-Fauré, Rebecca, Powell, Julie, Jonckheere, Fabien, Lanté, Eric, Denarier, Leticia, Peris, Chi Hung, Nguyen, Alain, Buisson, Laurence, Lafanechère, and Annie, Andrieux

Subjects
Pharmacology, cognitive abilities, MAP6, therapeutics, cytoskeleton, LIM kinase, actin, Original Research, microtubule
Abstract

The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.

Published
2020

14. AutoNeuriteJ: An ImageJ plugin for measurement and classification of neuritic extensions

Author

Jacques Brocard, Jean-Christophe Deloulme, Sylvie Gory-Fauré, Anne Beghin, Annie Andrieux, Benoit Boulan, Eric Denarier, Charlotte Ravanello, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), National University of Singapore (NUS), This work was supported by Institut National de la Santé et de la recherche Médicale, Commissariat à l’Energie Atiomique et aux Energies Alternatives, Université Grenoble Alpes and by awards from the French Agence Nationale de la Recherche to A.A. (2017-CE11-0026 MAMAs). https://www.inserm.fr/ http://www.cea.fr/ https://www.univ-grenoble-alpes.fr/ https://anr.fr/., ANR-17-CE11-0026,MAMAs,Coordination des microtubules et de l'actine par les MAPs structurales(2017), Bodescot, Myriam, and Coordination des microtubules et de l'actine par les MAPs structurales - - MAMAs2017 - ANR-17-CE11-0026 - AAPG2017 - VALID

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Imagej plugin, Biochemistry, Hippocampus, Mice, 0302 clinical medicine, Nerve Fibers, Animal Cells, Image Processing, Computer-Assisted, MAP6, Cells, Cultured, Neurons, Mice, Knockout, 0303 health sciences, Neuronal Morphology, Cell Differentiation, medicine.anatomical_structure, Medicine, Cellular Types, Microtubule-Associated Proteins, Neuronal Differentiation, Research Article, Neurite, Imaging Techniques, Science, Neurogenesis, [SCCO.COMP]Cognitive science/Computer science, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Research and Analysis Methods, 03 medical and health sciences, [SCCO.COMP] Cognitive science/Computer science, Tubulins, medicine, Neurites, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Cell Proliferation, Morphometry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuronal Growth, Biology and Life Sciences, Proteins, Cell Biology, Neuronal Dendrites, Axons, Cytoskeletal Proteins, nervous system, Cellular Neuroscience, Neuron, Neuroscience, 030217 neurology & neurosurgery, Software, Developmental Biology
Abstract

Morphometry characterization is an important procedure in describing neuronal cultures and identifying phenotypic differences. This task usually requires labor-intensive measurements and the classification of numerous neurites from large numbers of neurons in culture. To automate these measurements, we wrote AutoNeuriteJ, an imageJ/Fiji plugin that measures and classifies neurites from a very large number of neurons. We showed that AutoNeuriteJ is able to detect variations of neuritic growth induced by several compounds known to affect the neuronal growth. In these experiments measurement of more than 5000 mouse neurons per conditions was obtained within a few hours. Moreover, by analyzing mouse neurons deficient for the microtubule associated protein 6 (MAP6) and wild type neurons we illustrate that AutoNeuriteJ is capable to detect subtle phenotypic difference in axonal length. Overall the use of AutoNeuriteJ will provide rapid, unbiased and accurate measurement of neuron morphologies.

Published
2020
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15. Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction

Author

Sylvie Gory-Fauré, Annie Andrieux, Mathilde Chivet, Christophe Bosc, Laura Pietrangelo, Julie Brocard, Muriel Sébastien, Isabelle Marty, Perrine Aubin, Benoît Giannesini, Anne Fourest-Lieuvin, John Rendu, Jacques Brocard, Simona Boncompagni, Julien Fauré, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), University 'G. d'Annunzio' of Chieti-Pescara [Chieti], INSERM U836, équipe 1, Physiopathologie du cytosquelette, Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Université de Montpellier (UM), Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre lesMyopathies (AFM-Téléthon) to MS, PA, and IM, and from Italian Ministry ofHealth - GR2011-02352681 to SB, Giannesini, Benoit, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Male, 0301 basic medicine, lcsh:Diseases of the musculoskeletal system, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Triad, Sarcoplasmic reticulum, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, Mice, 03 medical and health sciences, Microtubule, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Orthopedics and Sports Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Calcium Signaling, MAP6, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Calcium release, Chemistry, Myogenesis, Microtubule-associated protein, Muscle weakness, Skeletal muscle, Cell Biology, Muscle atrophy, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Muscle contraction, Knockout mouse, Female, medicine.symptom, lcsh:RC925-935, Microtubule-Associated Proteins, Gene Deletion
Abstract

Background The skeletal muscle fiber has a specific and precise intracellular organization which is at the basis of an efficient muscle contraction. Microtubules are long known to play a major role in the function and organization of many cells, but in skeletal muscle, the contribution of the microtubule cytoskeleton to the efficiency of contraction has only recently been studied. The microtubule network is dynamic and is regulated by many microtubule-associated proteins (MAPs). In the present study, the role of the MAP6 protein in skeletal muscle organization and function has been studied using the MAP6 knockout mouse line. Methods The presence of MAP6 transcripts and proteins was shown in mouse muscle homogenates and primary culture using RT-PCR and western blot. The in vivo evaluation of muscle force of MAP6 knockout (KO) mice was performed on anesthetized animals using electrostimulation coupled to mechanical measurement and multimodal magnetic resonance. The impact of MAP6 deletion on microtubule organization and intracellular structures was studied using immunofluorescent labeling and electron microscopy, and on calcium release for muscle contraction using Fluo-4 calcium imaging on cultured myotubes. Statistical analysis was performed using Student’s t test or the Mann-Whitney test. Results We demonstrate the presence of MAP6 transcripts and proteins in skeletal muscle. Deletion of MAP6 results in a large number of muscle modifications: muscle weakness associated with slight muscle atrophy, alterations of microtubule network and sarcoplasmic reticulum organization, and reduction in calcium release. Conclusion Altogether, our results demonstrate that MAP6 is involved in skeletal muscle function. Its deletion results in alterations in skeletal muscle contraction which contribute to the global deleterious phenotype of the MAP6 KO mice. As MAP6 KO mouse line is a model for schizophrenia, our work points to a possible muscle weakness associated to some forms of schizophrenia.

Published
2018
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16. Omics analysis of mouse brain models of human diseases

Author

Elodie Mansour, Béatrice Alescio-Lautier, Yoon H. Cho, Veronique Paban, Sylvie Gory-Fauré, Susanna Pietropaolo, David Blum, Claude Villard, Béatrice Loriod, Ali Gharbi, Luc Buée, Laboratoire de Neurosciences intégratives et adaptatives (LNIA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Alzheimer & Tauopathies (Equipe 1), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), 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), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer & Tauopathies [JPArc], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Proteomics, 0301 basic medicine, Huntington, Autism, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene regulatory network, Mice, Transgenic, Network, Genomics, Biology, Transcriptome, Biological pathway, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, Animals, Humans, Gene Regulatory Networks, Parkinson, Gene, Mice, Knockout, Brain Diseases, Behavior, Animal, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Gene Expression Profiling, Mental Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, Proteomic, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Neurodegenerative Diseases, Amyloidosis, General Medicine, Gene expression profiling, Disease Models, Animal, Tauopathy, 030104 developmental biology, Transcriptomic, Genetically Engineered Mouse, [SCCO.PSYC]Cognitive science/Psychology, Schizophrenia, Metabolic Networks and Pathways, 030217 neurology & neurosurgery
Abstract

International audience; The identification of common gene/protein profiles related to brain alterations, if they exist, may indicate theconvergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse linesmodelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, includingtranscriptomic and proteomic methods, were used. The gene/protein lists were used for inter-diseasecomparisons and further functional and network investigations. When the inter-disease comparison was performedusing the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreasedrapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was sharedamong 4 disorders, providing strong evidence that a common molecular signature does not exist among braindiseases. The inter-disease comparison of functional processes showed the involvement of a fewmajor biologicalprocesses indicating that brain diseases of diverse aetiologies might utilize common biological pathways in thenervous system, without necessarily involving similar molecules.

Published
2017
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17. Short- and long-term efficacy of electroconvulsive stimulation in animal models of depression: The essential role of neuronal survival

Author

Christophe Porcher, Gaëlle Dall’Igna, Anne-Sophie Nguon, Sylvie Gory-Fauré, Eric Denarier, Christophe Heinrich, Nicolas Chauliac, Jean-Christophe Deloulme, Sabine Brugière, Jérôme Holtzmann, Julie Jonckheere, Yohann Couté, Celia Lentini, Jacques Brocard, Marie-Françoise Suaud-Chagny, Albane Pelluet, Annie Andrieux, Institut Neurosciences, Université Grenoble Alpes (UGA), Mécanismes d'expression cellulaire des effecteurs humoraux, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psymobile, Service Hospitalo-Universitaire du pôle Ouest, Centre Hospitalier Le Vinatier, Bron Cedex, Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Groupe Physiopathologie du Cytosquelette (GPC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etude de la dynamique des protéomes (EDyP), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-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), Experimental Epilepsy Group, University of Freiburg [Freiburg], Institut de neurobiologie de la Méditerranée (INMED), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Vulnérabilité à la schizophrénie : des bases neurobiologiques à la thérapeutique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR19-Centre Hospitalier le Vinatier [Bron], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Transduction du signal : signalisation calcium, phosphorylation et inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Etude de la dynamique des protéomes (EDyP ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Groupe d'Etude du Stress et des Interactions Neuro-Digestives (GESIND), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut Fédératif des Neurosciences de Lyon (IFNL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Centre Hospitalier le Vinatier [Bron]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Grenoble Institut des Neurosciences (GIN), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Time Factors, Cell Survival, Neurogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biophysics, Synaptogenesis, Antidepressant, Adult neurogenesis, Hippocampus, MAP6 KO mice, lcsh:RC321-571, Mice, 03 medical and health sciences, 0302 clinical medicine, Electroconvulsive therapy, Animal models of depression, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neuroplasticity, Genetic model, medicine, Animals, Electroconvulsive Therapy, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurons, Depression, business.industry, General Neuroscience, ECS, ECT, medicine.disease, 3. Good health, Disease Models, Animal, Treatment Outcome, 030104 developmental biology, Schizophrenia, Major depressive disorder, Neurology (clinical), business, Microtubule-Associated Proteins, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background Severe and medication-resistant psychiatric diseases, such as major depressive disorder, bipolar disorder or schizophrenia, can be effectively and rapidly treated by electroconvulsive therapy (ECT). Despite extensive long-standing clinical use, the neurobiological mechanisms underlying the curative action of ECT remain incompletely understood. Objective Unravel biological basis of electroconvulsive stimulation (ECS) efficacy, the animal equivalent of ECT. Methods Using MAP6 KO mouse, a genetic model that constitutively exhibits features relevant to some aspects of depression; we analyzed the behavioral and biological consequences of ECS treatment alone (10 stimulations over a 2-week period) and associated with a continuation protocol (2 stimulations per week for 5 weeks). Results ECS treatment had a beneficial effect on constitutive behavioral defects. We showed that behavioral improvement is associated with a strong increase in the survival and integration of neurons born before ECS treatment. Retroviral infection revealed the larger number of integrated neurons to exhibit increased dendritic complexity and spine density, as well as remodeled synapses. Furthermore, our results show that ECS triggers a cortical increase in synaptogenesis. A sustained newborn neuron survival rate, induced by ECS treatment, is associated with the behavioral improvement, but relapse occurred 40 days after completing the ECS treatment. However, a 5-week continuation protocol following the initial ECS treatment led to persistent improvement of behavior correlated with sustained rate survival of newborn neurons. Conclusion Altogether, these results reveal that increased synaptic connectivity and extended neuronal survival are key to the short and long-term efficacy of ECS.

Published
2018
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18. Phase from defocus

Author

Eric Denarier, Ondrej Mandula, Lionel Hervé, Anne Fourest-Lieuvin, Sophie Morales, Sylvie Gory-Fauré, Angélique Vinit, and Cédric Allier

Subjects
Microscope, Computer science, business.industry, Phase (waves), Phase image, law.invention, Image (mathematics), Light source, Optics, Transmission (telecommunications), law, Simplicity (photography), Phase imaging, business
Abstract

We present a simple and compact phase imaging microscope for long-term observation of non-absorbing biological samples such as unstained cells in nutritive media. The phase image is obtained from a single defocused image taken with a standard wide-field microscope. Using a semi-coherent light source allows us to computationally re-focus image post-acquisition and recover both phase and transmission of the complex specimen. The simplicity of the system reduces both the cost and its physical size and allows a long-term observation of samples directly in a standard biological incubator. The low cost of the system can contribute to the democratization of science by allowing to perform complex long-term biological experiments to the laboratories with constrained budget. In this proceeding we present several results taken with our prototype and discuss the possibilities and limitations of our system.

Published
2018
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19. Brain stimulation for psychiatric disorders: Insight from animal models

Author

Marie-Françoise Suaud-Chagny, Dimitri De Bundel, Frédéric Haesebaert, Robrecht Dockx, Sylvie Gory-Fauré, and Vincent Van Waes

Subjects
medicine.medical_specialty, Transcranial direct-current stimulation, business.industry, medicine.medical_treatment, Stimulation, Cognition, Extinction (psychology), Transcranial magnetic stimulation, Psychiatry and Mental health, Arts and Humanities (miscellaneous), Brain stimulation, Medicine, Fear conditioning, business, Psychiatry, Depression (differential diagnoses)
Abstract

In this symposium, we will tackle several examples of studies conducted in animal models to unravel the mode of action of different methods of non-invasive brain stimulation used to treat psychiatric disorders in human. First, Sylvie Gory-Faure will highlight the essential role of neural survival for short- and long-term efficacy of electroconvulsive stimulation in an animal model of depression (MAP6 KO mouse). Then, Vincent Van Waes will present behavioral and neurobiological data on the beneficial impact of repeated anodal transcranial direct stimulation on cognition, depression- and addiction-related behaviors in mice. Robrecht Dockx will describe a new accelerated high frequency (aHF) repetitive transcranial magnetic stimulation protocol tested in dogs. Finally, Dimitri De Bundel will talk about the effects of transcranial direct current stimulation to modulate fear extinction in a mouse model based on auditory fear conditioning. To conclude, the necessity to carry out translational studies to accelerate the development of brain stimulation techniques that have a strong therapeutic potential in human will be discussed.

Published
2019
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20. Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

Author

Jean-Christophe Deloulme, Sylvie Gory-Fauré, Franck Mauconduit, Sophie Chauvet, Julie Jonckheere, Benoit Boulan, Erik Mire, Jing Xue, Marion Jany, Caroline Maucler, Agathe Deparis, Olivier Montigon, Alexia Daoust, Barbier, Emmanuel L., Christophe Bosc, Nicole Déglon, Jacques Brocard, Eric Denarier, Isabelle Le Brun, Karin Pernet-Gallay, Isabelle Vilgrain, Phillip Robinson, Hana Lahrech, Fanny Mann, Annie Andrieux, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Neurosciences, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, Centre de recherche en neurosciences de Lyon (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), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratory of Developmental Biology, McGill University = Université McGill [Montréal, Canada], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire de développement et vieillissement de l'endothélium, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Inserm U836, équipe 7, Nanomédecine et cerveau, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), 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), 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)-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), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of Sydney, Lausanne University Hospital, Lausanne university hospital, INSERM, CEA, Univ. Grenoble Alpes, National Health and Medical Research Council of Australia, ANR-10-BLAN-1202,CBioS,Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale(2010), and ANR-11-INBS-0006,FLI,France Life Imaging(2011)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Fornix, Brain, Semaphorins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, Article, src Homology Domains, Animals, Axons/metabolism, Brain/metabolism, Brain/pathology, Diffusion Tensor Imaging, Fornix, Brain/embryology, Fornix, Brain/metabolism, Glycoproteins/metabolism, HEK293 Cells, Humans, Magnetic Resonance Imaging, Membrane Proteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Microtubule-Associated Proteins/genetics, Neural Pathways/embryology, Neural Pathways/metabolism, Neurites/metabolism, Neuroanatomical Tract-Tracing Techniques, Neurons/metabolism, Organ Size, Neural Pathways, Neurites, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Glycoproteins, Neurons, Brain, Membrane Proteins, Development of the nervous system, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Axons, Cytoskeletal proteins, nervous system, Microtubule-Associated Proteins, Cell signalling
Abstract

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts., Loss of the structural microtubule-associated protein 6 (MAP6) leads to neuronal differentiation defects that are independent of MAP6's microtubule-binding properties. Here the authors establish a functional link between MAP6 and Semaphorin 3E signalling for proper formation of the fornix of the brain.

Published
2015
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21. Auditory steady state responses in rodents, a new tool for drug discovery in schizophrenia?

Author

C. Touller, R. Maury, Annie Andrieux, Sylvie Gory-Fauré, B. Mandé, C. Dumont, C. Roucard, V. Duveau, A. Evrard, Y. Roche, and B. Pouyatos

Subjects
Pharmacology, Psychiatry and Mental health, Steady state (electronics), Neurology, Drug discovery, Schizophrenia (object-oriented programming), Pharmacology (medical), Neurology (clinical), Psychology, Neuroscience, Biological Psychiatry
Published
2017
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