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32 results on '"Sylvie Gory-Fauré"'

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. 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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5. 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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6. 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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7. Non-microtubular localizations of microtubule-associated protein 6 (MAP6).

Author

Sylvie Gory-Fauré, Vanessa Windscheid, Jacques Brocard, Sylvie Montessuit, Ryouhei Tsutsumi, Eric Denarier, Yuko Fukata, Christophe Bosc, Julie Delaroche, Nora Collomb, Masaki Fukata, Jean-Claude Martinou, Karin Pernet-Gallay, and Annie Andrieux

Subjects
Medicine, Science
Abstract

MAP6 proteins (MAP6s), which include MAP6-N (also called Stable Tubule Only Polypeptide, or STOP) and MAP6d1 (MAP6 domain-containing protein 1, also called STOP-Like protein 21 kD, or SL21), bind to and stabilize microtubules. MAP6 deletion in mice severely alters integrated brain functions and is associated with synaptic defects, suggesting that MAP6s may also have alternative cellular roles. MAP6s reportedly associate with the Golgi apparatus through palmitoylation of their N-terminal domain, and specific isoforms have been shown to bind actin. Here, we use heterologous systems to investigate several biochemical properties of MAP6 proteins. We demonstrate that the three N-terminal cysteines of MAP6d1 are palmitoylated by a subset of DHHC-type palmitoylating enzymes. Analysis of the subcellular localization of palmitoylated MAP6d1, including electron microscopic analysis, reveals possible localization to the Golgi and the plasma membrane but no association with the endoplasmic reticulum. Moreover, we observed localization of MAP6d1 to mitochondria, which requires the N-terminus of the protein but does not require palmitoylation. We show that endogenous MAP6d1 localized at mitochondria in mature mice neurons as well as at the outer membrane and in the intermembrane space of purified mouse mitochondria. Last, we found that MAP6d1 can multimerize via a microtubule-binding module. Interestingly, most of these properties of MAP6d1 are shared by MAP6-N. Together, these results describe several properties of MAP6 proteins, including their intercellular localization and multimerization activity, which may be relevant to neuronal differentiation and synaptic functions.

Published
2014
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8. How morphological constraints affect axonal polarity in mouse neurons.

Author

Sophie Roth, Mariano Bisbal, Jacques Brocard, Ghislain Bugnicourt, Yasmina Saoudi, Annie Andrieux, Sylvie Gory-Fauré, and Catherine Villard

Subjects
Medicine, Science
Abstract

Neuronal differentiation is under the tight control of both biochemical and physical information arising from neighboring cells and micro-environment. Here we wished to assay how external geometrical constraints applied to the cell body and/or the neurites of hippocampal neurons may modulate axonal polarization in vitro. Through the use of a panel of non-specific poly-L-lysine micropatterns, we manipulated the neuronal shape. By applying geometrical constraints on the cell body we provided evidence that centrosome location was not predictive of axonal polarization but rather follows axonal fate. When the geometrical constraints were applied to the neurites trajectories we demonstrated that axonal specification was inhibited by curved lines. Altogether these results indicated that intrinsic mechanical tensions occur during neuritic growth and that maximal tension was developed by the axon and expressed on straight trajectories. The strong inhibitory effect of curved lines on axon specification was further demonstrated by their ability to prevent formation of multiple axons normally induced by cytochalasin or taxol treatments. Finally we provided evidence that microtubules were involved in the tension-mediated axonal polarization, acting as curvature sensors during neuronal differentiation. Thus, biomechanics coupled to physical constraints might be the first level of regulation during neuronal development, primary to biochemical and guidance regulations.

Published
2012
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10. 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

11. 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

13. 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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14. 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

16. 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

17. 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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18. 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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19. 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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20. 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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21. 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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22. MAP6 dosage controls cognitive abilities

Author

Mohamed Saoud, Marie-Françoise Suaud-Chagny, Annie Andrieux, Jacques Brocard, Julien Volle, Jerome Brunelin, Sylvie Gory-Fauré, Schizophrenies Débutantes et Résistantes : de la Physiopathologie à la Thérapeutique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Centre Hospitalier le Vinatier [Bron], Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-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), Région Rhône-Alpes France ('Cluster 11: Age-Handicap-Vieillissement'), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and 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)-Grenoble Institut des Neurosciences (GIN)

Subjects
Male, behavioural phenotype, Heterozygote, medicine.medical_specialty, Psychosis, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Allele, Amphetamine, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Maternal deprivation, Behavior, Animal, neurodevelopment, business.industry, Maternal Deprivation, animal model, Cognitive disorder, behavioral phenotype, Wild type, Regular Article, Heterozygote advantage, medicine.disease, Mice, Inbred C57BL, schizophrenia, Disease Models, Animal, Psychiatry and Mental health, Phenotype, Endocrinology, Schizophrenia, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, gene x environment interaction, Gene-Environment Interaction, Cognition Disorders, business, Microtubule-Associated Proteins, Neuroscience, Locomotion, 030217 neurology & neurosurgery, microtubule, medicine.drug
Abstract

International audience; Background: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods : Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results : Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion : Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments.

Published
2012
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23. Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy

Author

Veerle Janssens, Sylvie Gory-Fauré, Saadi Khochbin, Eloi Bahembera, Matthieu Rousset, Michel De Waard, Florian Lesage, Caroline Lambrecht, Abir Tadmouri, Maud Barbado, Karin Pernet-Gallay, Shigeki Kiyonaka, Ricardo E. Dolmetsch, Annie Andrieux, Michel Ronjat, Yasuo Mori, Sylvain Baulande, Seishiro Sawamura, Christophe Arnoult, Katell Fablet, Takafumi Miki, Karin Sadoul, and Satoshi Akiyama

Subjects
Regulation of gene expression, 0303 health sciences, General Immunology and Microbiology, biology, General Neuroscience, Repressor, Promoter, CACNB4, Molecular biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Histone H3, 0302 clinical medicine, Gene expression, biology.protein, Molecular Biology, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology, Histone binding
Abstract

Calcium current through voltage-gated calcium channels (VGCC) controls gene expression. Here, we describe a novel signalling pathway in which the VGCC Cacnb4 subunit directly couples neuronal excitability to transcription. Electrical activity induces Cacnb4 association to Ppp2r5d, a regulatory subunit of PP2A phosphatase, followed by (i) nuclear translocation of Cacnb4/Ppp2r5d/PP2A, (ii) association with the tyrosine hydroxylase (TH) gene promoter through the nuclear transcription factor thyroid hormone receptor alpha (TRα), and (iii) histone binding through association of Cacnb4 with HP1γ concomitantly with Ser(10) histone H3 dephosphorylation by PP2A. This signalling cascade leads to TH gene repression by Cacnb4 and is controlled by the state of interaction between the SH3 and guanylate kinase (GK) modules of Cacnb4. The human R482X CACNB4 mutation, responsible for a form of juvenile myoclonic epilepsy, prevents association with Ppp2r5 and nuclear targeting of the complex by altering Cacnb4 conformation. These findings demonstrate that an intact VGCC subunit acts as a repressor recruiting platform to control neuronal gene expression.

Published
2012
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24. Neuronal Architectures with Axo-dendritic Polarity above Silicon Nanowires

Author

Sophie Roth, Sylvie Gory-Fauré, Catherine Villard, Mariano Bisbal, Ghislain Bugnicourt, Jacques Brocard, 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)-Institut Néel (NEEL), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-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 Néel (NEEL), 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), Thermodynamique et biophysique des petits systèmes (NEEL - TPS), Institut Néel (NEEL), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Nanoscience Foundation, Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Grenoble Institut des Neurosciences (GIN), Thermodynamique et biophysique des petits systèmes (TPS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Andrieux, Annie

Subjects
Silicon, MESH: Axons, Materials science, MESH: Microscopy, Electron, Scanning, Polarity (physics), [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], MESH: Neurons, Nanowire, 02 engineering and technology, Cellular level, MESH: Dendrites, Signal, Biomaterials, Mice, 03 medical and health sciences, Animals, Nanotechnology, Automatic gain control, MESH: Animals, General Materials Science, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Silicon nanowires, MESH: Mice, MESH: Nanotechnology, Cells, Cultured, 030304 developmental biology, Neurons, MESH: Silicon, 0303 health sciences, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Nanowires, business.industry, Dendrites, General Chemistry, 021001 nanoscience & nanotechnology, Axons, nervous system, MESH: Nanowires, Microscopy, Electron, Scanning, Optoelectronics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 0210 nano-technology, business, MESH: Cells, Cultured, Biotechnology
Abstract

International audience; An approach is developped to gain control over the polarity of neuronal networks at the cellular level by physically constraining cell development by the use of micropatterns. It is demonstrated that the position and path of individual axons, the cell extension that propagates the neuron output signal, can be chosen with a success rate higher than 85%. This allows the design of small living computational blocks above silicon nanowires.

Published
2012
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25. 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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26. 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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27. Neuronal transport defects of the MAP6 KO mouse - a model of schizophrenia - and alleviation by Epothilone D treatment, as observed using MEMRI

Author

Sylvain Bohic, Annie Andrieux, Yasmina Saoudi, Emmanuel L. Barbier, Alexia Daoust, Jean-Christophe Deloulme, Clément Debacker, Sylvie Gory-Fauré, INSERM U836, équipe 6, Rayonnement synchrotron et recherche médicale, 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), European Synchrotron Radiation Facility (ESRF)-Grenoble Institut des Neurosciences (GIN), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, 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)-Bruker Biospin MRI, Bruker Biospin MRI-Bruker Biospin MRI, 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), European Project, Andrieux, Annie, BLANC - Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale - - CBioS2010 - ANR-10-BLAN-1202 - BLANC - VALID, Région Rhône-Alpes - Cluster HVN, and INCOMING

Subjects
medicine.medical_specialty, Cognitive Neuroscience, Contrast Media, MEMRI, Neurotransmission, Somatosensory system, Synaptic Transmission, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Internal medicine, medicine, Animals, Humans, MAP6, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuronal transport, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Manganese, medicine.diagnostic_test, Chemistry, Magnetic resonance imaging, Somatosensory Cortex, Magnetic Resonance Imaging, Tubulin Modulators, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Treatment Outcome, Neurology, Epothilones, Synaptic plasticity, Axoplasmic transport, Schizophrenia, Epothilone D, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Microtubule-Associated Proteins, 030217 neurology & neurosurgery, Neuronal tract
Abstract

International audience; The MAP6 (microtubule-associated protein 6) KO mouse is a microtubule-deficient model of schizophrenia that exhibits severe behavioral disorders that are associated with synaptic plasticity anomalies. These defects are alleviated not only by neuroleptics, which are the gold standard molecules for the treatment of schizophrenia, but also by Epothilone D (Epo D), which is a microtubule-stabilizing molecule. To compare the neuronal transport between MAP6 KO and wild-type mice and to measure the effect of Epo D treatment on neuronal transport in KO mice, MnCl2 was injected in the primary somatosensory cortex. Then, using manganese-enhanced magnetic resonance imaging (MEMRI), we followed the propagation of Mn(2+) through axonal tracts and brain regions that are connected to the somatosensory cortex. In MAP6 KO mice, the measure of the MRI relative signal intensity over 24h revealed that the Mn(2+) transport rate was affected with a stronger effect on long-range and polysynaptic connections than in short-range and monosynaptic tracts. The chronic treatment of MAP6 KO mice with Epo D strongly increased Mn(2+) propagation within both mono- and polysynaptic connections. Our results clearly indicate an in vivo deficit in neuronal Mn(2+) transport in KO MAP6 mice, which might be due to both axonal transport defects and synaptic transmission impairments. Epo D treatment alleviated the axonal transport defects, and this improvement most likely contributes to the positive effect of Epo D on behavioral defects in KO MAP6 mice.

Published
2014
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28. Living ordered neural networks as model systems for signal processing

Author

Sophie Roth, Julie Brocard, Claude Villard, Pierre-Olivier Amblard, Sylvie Gory-Fauré, and Guillaume Becq

Subjects
Signal processing, Theoretical computer science, Artificial neural network, Noise (signal processing), business.industry, Computer science, Pooling, Tree (data structure), medicine.anatomical_structure, nervous system, medicine, Biological neural network, Soma, Artificial intelligence, Neuron, business
Abstract

Neural circuit architecture is a fundamental characteristic of the brain, and how architecture is bound to biological functions is still an open question. Some neuronal geometries seen in the retina or the cochlea are intriguing: information is processed in parallel by several entities like in "pooling" networks which have recently drawn the attention of signal processing scientists. These systems indeed exhibit the noise-enhanced processing effect, which is also actively discussed in the neuroscience community at the neuron scale. The aim of our project is to use in-vitro ordered neuron networks as living paradigms to test ideas coming from the computational science. The different technological bolts that have to be solved are enumerated and the first results are presented. A neuron is a polarised cell, with an excitatory axon and a receiving dendritic tree. We present how soma confinement and axon differentiation can be induced by surface functionalization techniques. The recording of large neuron networks, ordered or not, is also detailed and biological signals shown. The main difficulty to access neural noise in the case of weakly connected networks grown on micro electrode arrays is explained. This open the door to a new detection technology suitable for sub-cellular analysis and stimulation, whose development will constitute the next step of this project.

Published
2007
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29. Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia

Author

Mélina Bégou, Gerhard Höfle, Didier Job, Marie-Françoise Suaud-Chagny, Sylvie Gory-Fauré, Pekka Kujala, Annie Schweitzer, Philippe Brun, Paul A. Salin, Bastien Pachoud, Annie Andrieux, 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, Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), The Netherlands Cancer Institute, German Research Center for Biotechnology, and Andrieux, Annie

Subjects
Male, MESH: Hippocampus, MESH: Neurons, Hippocampus, Synaptic Transmission, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, MAP6, MESH: Neuronal Plasticity, Maternal Behavior, Cells, Cultured, Mice, Knockout, Neurons, 0303 health sciences, Mice, Inbred BALB C, Neuronal Plasticity, Behavior, Animal, MESH: Electric Stimulation, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Tubulin Modulators, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Exploratory Behavior, Microtubule-Associated Proteins, medicine.drug, MESH: Cells, Cultured, MESH: Mice, Inbred BALB C, Biology, Synaptic vesicle, 03 medical and health sciences, Glutamatergic, Dopamine, MESH: Tubulin Modulators, medicine, MESH: Synaptic Transmission, Animals, MESH: Epothilones, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Excitatory Postsynaptic Potentials, MESH: Mice, Biological Psychiatry, 030304 developmental biology, Excitatory Postsynaptic Potentials, Actin cytoskeleton, Electric Stimulation, MESH: Male, MESH: Schizophrenia, Disease Models, Animal, MESH: Microtubule-Associated Proteins, Synaptic fatigue, Epothilones, MESH: Maternal Behavior, Synaptic plasticity, Exploratory Behavior, Schizophrenia, MESH: Disease Models, Animal, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Recent data suggest that cytoskeletal defects may play a role in schizophrenia. We previously imitated features of schizophrenia in an animal model by disrupting gene coding for a microtubule-associated protein called STOP. STOP-null mice display synaptic defects in glutamatergic neurons, hyper-dopaminergy, and severe behavioral disorders. Synaptic and behavioral deficits are amended by neuroleptic treatment in STOP-null mice, providing an attractive model to test new antipsychotic agents. We examined the effects of a taxol-related microtubule stabilizer, epothilone D. METHODS: Mice were treated either with vehicle alone or with epothilone D. Treatment effects on synaptic function were assessed using electron-microscopy quantification of synaptic vesicle pools and electrophysiology in the CA1 region of the hippocampus. Dopamine transmission was investigated using electrochemical assays. Behavior was principally assessed using tests of maternal skills. RESULTS: In STOP-null mice, treatment with epothilone D increased synaptic vesicle pools, ameliorated both short- and long-term forms of synaptic plasticity in glutamatergic neurons, and had a dramatic beneficial effect on mouse behavior. CONCLUSIONS: A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia.

Published
2006
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30. Phosphorylation of microtubule-associated protein STOP by calmodulin kinase II

Author

Laurent Blanchoin, Paul A. Salin, Fabrice Dufour, Christophe Bosc, Leticia Peris, Anne Fourest-Lieuvin, Didier Job, Julie Baratier, Annie Andrieux, Jacques Brocard, Sylvie Gory-Fauré, 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, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
multifunctional enzyme, actin binding, Microtubule-associated protein, microtubule stabilization, Biology, Biochemistry, Hippocampus, Microtubules, 03 medical and health sciences, Mice, 0302 clinical medicine, STOP protein, Calmodulin, Microtubule, Ca2+/calmodulin-dependent protein kinase, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MAP6, Phosphorylation, Cytoskeleton, Molecular Biology, mouse, 030304 developmental biology, Neurons, 0303 health sciences, synaptic plasticity, Brain, cytoskeleton, Cell Biology, calmodulin kinase, neuron, Actins, Cell biology, Protein Transport, medicine.anatomical_structure, Microscopy, Fluorescence, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinases, Synapses, Neuron, mammalia, microtubule associated protein, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Microtubule-Associated Proteins, 030217 neurology & neurosurgery
Abstract

STOP proteins are microtubule-associated, calmodulin-regulated proteins responsible for the high degree of stabilization displayed by neuronal microtubules. STOP suppression in mice induces synaptic defects affecting both short and long term synaptic plasticity in hippocampal neurons. Interestingly, STOP has been identified as a component of synaptic structures in neurons, despite the absence of microtubules in nerve terminals, indicating the existence of mechanisms able to induce a translocation of STOP from microtubules to synaptic compartments. Here we have tested STOP phosphorylation as a candidate mechanism for STOP relocalization. We show that, both in vitro and in vivo, STOP is phosphorylated by the multifunctional enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), which is a key enzyme for synaptic plasticity. This phosphorylation occurs on at least two independent sites. Phosphorylated forms of STOP do not bind microtubules in vitro and do not co-localize with microtubules in cultured differentiating neurons. Instead, phosphorylated STOP co-localizes with actin assemblies along neurites or at branching points. Correlatively, we find that STOP binds to actin in vitro. Finally, in differentiated neurons, phosphorylated STOP co-localizes with clusters of synaptic proteins, whereas unphosphorylated STOP does not. Thus, STOP phosphorylation by CaMKII may promote STOP translocation from microtubules to synaptic compartments where it may interact with actin, which could be important for STOP function in synaptic plasticity.

Published
2006
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31. The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders

Author

Paul A. Salin, Christophe Bosc, Judith Klumperman, Didier Job, Muriel Vernet, Annie Schweitzer, Dominique Proietto, Eric Denarier, Pekka Kujala, Julie Baratier, Annie Andrieux, Hervé Pointu, and Sylvie Gory-Fauré

Subjects
Male, Biology, Neurotransmission, Synaptic vesicle, Microtubules, Synaptic Transmission, Mice, Microtubule, Neuroplasticity, Genetics, medicine, Animals, Humans, MAP6, Mice, Knockout, Neuronal Plasticity, Behavior, Animal, Brain, medicine.disease, Cell biology, Cold Temperature, Disease Models, Animal, Microscopy, Electron, Synaptic fatigue, Anti-Anxiety Agents, Schizophrenia, Synaptic plasticity, Synapses, Female, Microtubule-Associated Proteins, Developmental Biology, Antipsychotic Agents, Research Paper
Abstract

Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP−/− mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP−/− mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP−/− mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.

Published
2002

32. Role of vascular endothelial-cadherin in vascular morphogenesis

Author

Sylvie Gory-Fauré, Valérie Roullot, Philippe Huber, Isabelle Pignot-Paintrand, Hervé Pointu, Muriel Vernet, and Marie-Hélène Prandini

Subjects
Angiogenesis, Neovascularization, Physiologic, Allantois, Biology, Angioblast, Cadherins, Cell junction, Cell biology, Hematopoiesis, Vascular endothelial growth factor B, Dorsal aorta, Embryonic and Fetal Development, Mice, medicine.anatomical_structure, Phenotype, Antigens, CD, medicine, Morphogenesis, Animals, Blood islands, Endothelium, Vascular, Yolk sac, Molecular Biology, Developmental Biology
Abstract

Vascular endothelial (VE)-cadherin is an adhesive transmembrane protein specifically expressed at interendothelial junctions. Its extracellular domain exhibits Ca2+-dependent homophilic reactivity, promoting cell-cell recognition. Mice deficient in VE-cadherin die at mid-gestation resulting from severe vascular defects. At the early phases of vascular development (E8.5) of VE- cadherin-deficient embryos, in situ differentiation of endothelial cells was delayed although their differentiation program appeared normal. Vascularization was defective in the anterior part of the embryo, while dorsal aortae and vitelline and umbilical arteries formed normally in the caudal part. At E9.25, organization of endothelial cells into large vessels was incomplete and angiogenesis was impaired in mutant embryos. Defects were more severe in extraembryonic vasculature. Blood islands of the yolk sac and clusters of angioblasts in allantois failed to establish a capillary plexus and remained isolated. This was not due to defective cell-cell recognition as endothelial cells formed intercellular junctions, as shown by electron microscopy. These data indicate that VE-cadherin is dispensable for endothelial homophilic adhesion but is required for vascular morphogenesis.

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