29 results on '"Gory-Fauré S"'
Search Results
2. Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice
- Author
-
Pagnamenta, AT, Heemeryck, P, Martin, HC, Bosc, C, Peris, L, Uszynski, I, Gory-Fauré, S, Couly, S, Deshpande, C, Siddiqui, A, Elmonairy, AA, Consortium, WGS500, Consortium, Genomics England Research, Jayawant, S, Murthy, S, Walker, I, Loong, L, Bauer, P, Vossier, F, Denarier, E, Maurice, T, Barbier, EL, Deloulme, J-C, Taylor, JC, Blair, EM, Andrieux, A, Moutin, M-J, Oxford NIHR Biomedical Research Centre, [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]), The Wellcome Trust Sanger Institute [Cambridge], 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Guy's Hospital [London], Kings College Hospital, Ministry of Health [Koweït], John Radcliffe Hospital [Oxford University Hospital], Upton Hospital [Slough, Royaume-uni], Wexham Park Hospital [Slough, Royaume-Uni], Oxford University Hospitals NHS Trust, University of Oxford [Oxford], CENTOGENE AG, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), 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), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and University of Oxford
- Subjects
Neurons ,Immunoblotting ,Brain ,[SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis ,Cell Cycle Proteins ,Magnetic Resonance Imaging ,Mice ,Tubulin ,Microcephaly ,Animals ,Humans ,Tyrosine ,Cognitive Dysfunction ,Female ,General Article ,Carrier Proteins ,ComputingMilieux_MISCELLANEOUS - Abstract
Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28(*) and p.K13Nfs(*)18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology.
- Published
- 2019
3. P.1.g.014 - Auditory steady state responses in rodents, a new tool for drug discovery in schizophrenia?
- Author
-
Roucard, C., Pouyatos, B., Gory-Faure, S., Touller, C., Evrard, A., Maury, R., Dumont, C., Mandé, B., Andrieux, A., Roche, Y., and Duveau, V.
- Published
- 2017
- Full Text
- View/download PDF
4. Living ordered neural networks as model systems for signal processing
- Author
-
Villard, C., primary, Amblard, P. O., additional, Becq, G., additional, Gory-Fauré, S., additional, Brocard, J., additional, and Roth, S., additional
- Published
- 2007
- Full Text
- View/download PDF
5. Living ordered neural networks as model systems for signal processing.
- Author
-
Villard, C., Amblard, P. O., Becq, G., Gory-Fauré, S., Brocard, J., and Roth, S.
- Published
- 2007
- Full Text
- View/download PDF
6. Role of vascular endothelial-cadherin in vascular morphogenesis.
- Author
-
Gory-Fauré, S, Prandini, M H, Pointu, H, Roullot, V, Pignot-Paintrand, I, Vernet, M, and Huber, P
- 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.
- Published
- 1999
7. Stable GDP-tubulin islands rescue dynamic microtubules.
- Author
-
Bagdadi N, Wu J, Delaroche J, Serre L, Delphin C, De Andrade M, Carcel M, Nawabi H, Pinson B, Vérin C, Couté Y, Gory-Fauré S, Andrieux A, Stoppin-Mellet V, and Arnal I
- Subjects
- Animals, Guanosine Triphosphate metabolism, Humans, Microtubules metabolism, Tubulin metabolism, Tubulin genetics, Guanosine Diphosphate metabolism
- Abstract
Microtubules are dynamic polymers that interconvert between phases of growth and shrinkage, yet they provide structural stability to cells. Growth involves hydrolysis of GTP-tubulin to GDP-tubulin, which releases energy that is stored within the microtubule lattice and destabilizes it; a GTP cap at microtubule ends is thought to prevent GDP subunits from rapidly dissociating and causing catastrophe. Here, using in vitro reconstitution assays, we show that GDP-tubulin, usually considered inactive, can itself assemble into microtubules, preferentially at the minus end, and promote persistent growth. GDP-tubulin-assembled microtubules are highly stable, displaying no detectable spontaneous shrinkage. Strikingly, islands of GDP-tubulin within dynamic microtubules stop shrinkage events and promote rescues. Microtubules thus possess an intrinsic capacity for stability, independent of accessory proteins. This finding provides novel mechanisms to explain microtubule dynamics., (© 2024 Bagdadi et al.)
- Published
- 2024
- Full Text
- View/download PDF
8. Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease.
- Author
-
Peris L, Parato J, Qu X, Soleilhac JM, Lanté F, Kumar A, Pero ME, Martínez-Hernández J, Corrao C, Falivelli G, Payet F, Gory-Fauré S, Bosc C, Blanca Ramirez M, Sproul A, Brocard J, Di Cara B, Delagrange P, Buisson A, Goldberg Y, Moutin MJ, Bartolini F, and Andrieux A
- Subjects
- Animals, Humans, Mice, Microtubules, Peptides metabolism, Tyrosine metabolism, Alzheimer Disease metabolism, Tubulin metabolism
- 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
- Full Text
- View/download PDF
9. Cryo-EM Visualization of Neuronal Particles Inside Microtubules.
- Author
-
Gory-Fauré S, Delaroche J, Cuveillier C, Delphin C, and Arnal I
- Subjects
- Animals, Cryoelectron Microscopy methods, Hippocampus, Mice, Microtubules metabolism, Neurons
- 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., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
10. CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway.
- Author
-
Boulan B, Ravanello C, Peyrel A, Bosc C, Delphin C, Appaix F, Denarier E, Kraut A, Jacquier-Sarlin M, Fournier A, Andrieux A, Gory-Fauré S, and Deloulme JC
- Subjects
- Animals, Female, Fornix, Brain metabolism, Male, Mice, Nerve Tissue Proteins metabolism, Semaphorins metabolism, Fornix, Brain growth & development, Nerve Tissue Proteins genetics, Semaphorins genetics, 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., Competing Interests: BB, CR, AP, CB, CD, FA, ED, AK, MJ, AF, AA, SG, JD No competing interests declared, (© 2021, Boulan et al.)
- Published
- 2021
- Full Text
- View/download PDF
11. Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories.
- Author
-
Cuveillier C, Boulan B, Ravanello C, Denarier E, Deloulme JC, Gory-Fauré S, Delphin C, Bosc C, Arnal I, and Andrieux A
- 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cuveillier, Boulan, Ravanello, Denarier, Deloulme, Gory-Fauré, Delphin, Bosc, Arnal and Andrieux.)
- Published
- 2021
- Full Text
- View/download PDF
12. Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia.
- Author
-
Gory-Fauré S, Powell R, Jonckheere J, Lanté F, Denarier E, Peris L, Nguyen CH, Buisson A, Lafanechère L, and Andrieux A
- 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gory-Fauré, Powell, Jonckheere, Lanté, Denarier, Peris, Nguyen, Buisson, Lafanechère and Andrieux.)
- Published
- 2021
- Full Text
- View/download PDF
13. AutoNeuriteJ: An ImageJ plugin for measurement and classification of neuritic extensions.
- Author
-
Boulan B, Beghin A, Ravanello C, Deloulme JC, Gory-Fauré S, Andrieux A, Brocard J, and Denarier E
- Subjects
- Animals, Axons physiology, Cell Proliferation, Cells, Cultured, Hippocampus physiology, Mice, Mice, Knockout, Microtubule-Associated Proteins genetics, Neurogenesis physiology, Software, Image Processing, Computer-Assisted methods, Neurites metabolism, Neurons physiology
- 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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
- Full Text
- View/download PDF
14. MAP6 is an intraluminal protein that induces neuronal microtubules to coil.
- Author
-
Cuveillier C, Delaroche J, Seggio M, Gory-Fauré S, Bosc C, Denarier E, Bacia M, Schoehn G, Mohrbach H, Kulić I, Andrieux A, Arnal I, and Delphin C
- Subjects
- Animals, Mice, Microtubules metabolism, Models, Biological, Neurites, Neurons ultrastructure, Protein Binding, Protein Transport, Microtubule-Associated Proteins metabolism, Neurons metabolism
- Abstract
Neuronal activities depend heavily on microtubules, which shape neuronal processes and transport myriad molecules within them. Although constantly remodeled through growth and shrinkage events, neuronal microtubules must be sufficiently stable to maintain nervous system wiring. This stability is somehow maintained by various microtubule-associated proteins (MAPs), but little is known about how these proteins work. Here, we show that MAP6, previously known to confer cold stability to microtubules, promotes growth. More unexpectedly, MAP6 localizes in the lumen of microtubules, induces the microtubules to coil into a left-handed helix, and forms apertures in the lattice, likely to relieve mechanical stress. These features have not been seen in microtubules before and could play roles in maintaining axonal width or providing flexibility in the face of compressive forces during development., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2020
- Full Text
- View/download PDF
15. Dissociated features of social cognition altered in mouse models of schizophrenia: Focus on social dominance and acoustic communication.
- Author
-
Faure A, Nosjean A, Pittaras E, Duchêne A, Andrieux A, Gory-Fauré S, Charvériat M, and Granon S
- Subjects
- Animals, Antipsychotic Agents therapeutic use, Cognition drug effects, Disease Models, Animal, Dizocilpine Maleate toxicity, Excitatory Amino Acid Antagonists toxicity, Ketamine toxicity, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Schizophrenia drug therapy, Vocalization, Animal drug effects, Cognition physiology, Schizophrenia chemically induced, Schizophrenia metabolism, Social Behavior, Social Dominance, Vocalization, Animal physiology
- Abstract
Social and communication impairments are common features of psychiatric disorders. Animal models of schizophrenia display various social deficits due to difference in tests, mouse strains and drugs. Moreover, communication deficits have not been studied. Our objectives were to assess and compare three major features of social cognition in different mouse models of schizophrenia: interest for a social stimulus, organization and acceptance of social contact, and acoustic communication to question whether mouse models for schizophrenia with social dysfunction also exhibit vocal communication defects. To achieve these aims we treated acutely C57BL/6J mice either with MK-801 or ketamine and tested WT and microtubule-associated protein 6 -MAP6- KO mice in two complementary social tasks: the 3-chamber test which measures social motivation and the social interaction task -SIT- which relies on prefrontal cortex activity and measures the ability to organize and respond to a real interaction, and which promotes ultrasonic vocalizations. Our results reveal that schizophrenia models have intact interest for a social stimulus in the 3-chamber test. However, thanks to principal component analyses of social interaction data, we demonstrate that social motivation and the ability to act socially rely on distinct mechanisms in revealing a decrease in dominance and communication in pharmacological schizophrenia models along with social withdraw, classically observed in schizophrenia, in MK-801 model. In this latter model, some social parameters can be significantly improved by aripiprazole, an atypical antipsychotic. Our social protocol, combined with fine-tuned analysis, is expected to provide an innovative framework for testing future treatments in preclinical models. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'., (Copyright © 2018. Published by Elsevier Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
16. Short- and long-term efficacy of electroconvulsive stimulation in animal models of depression: The essential role of neuronal survival.
- Author
-
Jonckheere J, Deloulme JC, Dall'Igna G, Chauliac N, Pelluet A, Nguon AS, Lentini C, Brocard J, Denarier E, Brugière S, Couté Y, Heinrich C, Porcher C, Holtzmann J, Andrieux A, Suaud-Chagny MF, and Gory-Fauré S
- Subjects
- Animals, Depression genetics, Depression metabolism, Hippocampus cytology, Hippocampus physiology, Male, Mice, Mice, Knockout, Microtubule-Associated Proteins deficiency, Microtubule-Associated Proteins genetics, Neurogenesis physiology, Time Factors, Treatment Outcome, Cell Survival physiology, Depression therapy, Disease Models, Animal, Electroconvulsive Therapy methods, Neurons physiology
- 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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
17. Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction.
- Author
-
Sébastien M, Giannesini B, Aubin P, Brocard J, Chivet M, Pietrangelo L, Boncompagni S, Bosc C, Brocard J, Rendu J, Gory-Fauré S, Andrieux A, Fourest-Lieuvin A, Fauré J, and Marty I
- Subjects
- Animals, Calcium Signaling, Cells, Cultured, Female, Gene Deletion, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins metabolism, Microtubules metabolism, Muscle Contraction, Muscle Fibers, Skeletal physiology, Muscle Fibers, Skeletal ultrastructure, Sarcoplasmic Reticulum metabolism, Microtubule-Associated Proteins genetics, Muscle Fibers, Skeletal metabolism
- 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
- Full Text
- View/download PDF
18. A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines.
- Author
-
Peris L, Bisbal M, Martinez-Hernandez J, Saoudi Y, Jonckheere J, Rolland M, Sebastien M, Brocard J, Denarier E, Bosc C, Guerin C, Gory-Fauré S, Deloulme JC, Lanté F, Arnal I, Buisson A, Goldberg Y, Blanchoin L, Delphin C, and Andrieux A
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Cells, Cultured, Fluorescence Resonance Energy Transfer, Hippocampus cytology, Humans, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microtubule-Associated Proteins genetics, Microtubules metabolism, Neurons metabolism, Phosphorylation, Photobleaching, Actin Cytoskeleton metabolism, Dendrites metabolism, Microtubule-Associated Proteins metabolism, Neurons cytology
- Abstract
Emerging evidence indicates that microtubule-associated proteins (MAPs) are implicated in synaptic function; in particular, mice deficient for MAP6 exhibit striking deficits in plasticity and cognition. How MAP6 connects to plasticity mechanisms is unclear. Here, we address the possible role of this protein in dendritic spines. We find that in MAP6-deficient cortical and hippocampal neurons, maintenance of mature spines is impaired, and can be restored by expressing a stretch of the MAP6 sequence called Mc modules. Mc modules directly bind actin filaments and mediate activity-dependent stabilisation of F-actin in dendritic spines, a key event of synaptic plasticity. In vitro, Mc modules enhance actin filament nucleation and promote the formation of stable, highly ordered filament bundles. Activity-induced phosphorylation of MAP6 likely controls its transfer to the spine cytoskeleton. These results provide a molecular explanation for the role of MAP6 in cognition, enlightening the connection between cytoskeletal dysfunction, synaptic impairment and neuropsychiatric illnesses.
- Published
- 2018
- Full Text
- View/download PDF
19. MAP6 interacts with Tctex1 and Ca v 2.2/N-type calcium channels to regulate calcium signalling in neurons.
- Author
-
Brocard J, Dufour F, Gory-Fauré S, Arnoult C, Bosc C, Denarier E, Peris L, Saoudi Y, De Waard M, and Andrieux A
- Subjects
- Animals, Binding Sites, Cells, Cultured, Female, Hippocampus cytology, Mice, Mice, Knockout, Microtubule-Associated Proteins genetics, Protein Binding, Calcium Channels, N-Type metabolism, Calcium Signaling physiology, Dyneins metabolism, Microtubule-Associated Proteins metabolism, Neurons metabolism
- Abstract
MAP6 proteins were first described as microtubule-stabilizing agents, whose properties were thought to be essential for neuronal development and maintenance of complex neuronal networks. However, deletion of all MAP6 isoforms in MAP6 KO mice does not lead to dramatic morphological aberrations of the brain but rather to alterations in multiple neurotransmissions and severe behavioural impairments. A search for protein partners of MAP6 proteins identified Tctex1 - a dynein light chain with multiple non-microtubule-related functions. The involvement of Tctex1 in calcium signalling led to investigate it in MAP6 KO neurons. In this study, we show that functional Ca
v 2.2/N-type calcium channels are deficient in MAP6 KO neurons, due to improper location. We also show that MAP6 proteins interact directly with both Tctex1 and the C-terminus of Cav 2.2/N-type calcium channels. A balance of these two interactions seems to be crucial for MAP6 to modulate calcium signalling in neurons., (© 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)- Published
- 2017
- Full Text
- View/download PDF
20. 3D imaging of the brain morphology and connectivity defects in a model of psychiatric disorders: MAP6-KO mice.
- Author
-
Gimenez U, Boulan B, Mauconduit F, Taurel F, Leclercq M, Denarier E, Brocard J, Gory-Fauré S, Andrieux A, Lahrech H, and Deloulme JC
- Subjects
- Animals, Brain pathology, Disease Models, Animal, Female, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mice, Mice, Knockout, Microscopy, Fluorescence, Microtubule-Associated Proteins deficiency, Neural Pathways, Brain diagnostic imaging, Brain metabolism, Brain Mapping, Imaging, Three-Dimensional methods, Mental Disorders diagnosis, Mental Disorders etiology
- Abstract
In the central nervous system, microtubule-associated protein 6 (MAP6) is expressed at high levels and is crucial for cognitive abilities. The large spectrum of social and cognitive impairments observed in MAP6-KO mice are reminiscent of the symptoms observed in psychiatric diseases, such as schizophrenia, and respond positively to long-term treatment with antipsychotics. MAP6-KO mice have therefore been proposed to be a useful animal model for these diseases. Here, we explored the brain anatomy in MAP6-KO mice using high spatial resolution 3D MRI, including a volumetric T
1w method to image brain structures, and Diffusion Tensor Imaging (DTI) for white matter fiber tractography. 3D DTI imaging of neuronal tracts was validated by comparing results to optical images of cleared brains. Changes to brain architecture included reduced volume of the cerebellum and the thalamus and altered size, integrity and spatial orientation of some neuronal tracks such as the anterior commissure, the mammillary tract, the corpus callosum, the corticospinal tract, the fasciculus retroflexus and the fornix. Our results provide information on the neuroanatomical defects behind the neurological phenotype displayed in the MAP6-KO mice model and especially highlight a severe damage of the corticospinal tract with defasciculation at the location of the pontine nuclei.- Published
- 2017
- Full Text
- View/download PDF
21. Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.
- Author
-
Deloulme JC, Gory-Fauré S, Mauconduit F, Chauvet S, Jonckheere J, Boulan B, Mire E, Xue J, Jany M, Maucler C, Deparis AA, Montigon O, Daoust A, Barbier EL, Bosc C, Deglon N, Brocard J, Denarier E, Le Brun I, Pernet-Gallay K, Vilgrain I, Robinson PJ, Lahrech H, Mann F, and Andrieux A
- Subjects
- Animals, Brain metabolism, Brain pathology, Cytoskeletal Proteins, Diffusion Tensor Imaging, Fornix, Brain metabolism, Fornix, Brain pathology, HEK293 Cells, Humans, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Neural Pathways embryology, Neural Pathways metabolism, Neurites metabolism, Neuroanatomical Tract-Tracing Techniques, Organ Size, Semaphorins, src Homology Domains, Axons metabolism, Fornix, Brain embryology, Glycoproteins metabolism, Membrane Proteins metabolism, Microtubule-Associated Proteins genetics, Neurons metabolism
- 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.
- Published
- 2015
- Full Text
- View/download PDF
22. Non-microtubular localizations of microtubule-associated protein 6 (MAP6).
- Author
-
Gory-Fauré S, Windscheid V, Brocard J, Montessuit S, Tsutsumi R, Denarier E, Fukata Y, Bosc C, Delaroche J, Collomb N, Fukata M, Martinou JC, Pernet-Gallay K, and Andrieux A
- Subjects
- 3T3 Cells, Animals, COS Cells, Cell Membrane metabolism, Cells, Cultured, Chlorocebus aethiops, Golgi Apparatus metabolism, HEK293 Cells, Humans, Mice, Microtubules metabolism, Mitochondria metabolism, Neurons metabolism, Neurons ultrastructure, Protein Binding, Protein Multimerization, Protein Transport, Microtubule-Associated Proteins metabolism
- 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
- Full Text
- View/download PDF
23. Neuronal transport defects of the MAP6 KO mouse - a model of schizophrenia - and alleviation by Epothilone D treatment, as observed using MEMRI.
- Author
-
Daoust A, Bohic S, Saoudi Y, Debacker C, Gory-Fauré S, Andrieux A, Barbier EL, and Deloulme JC
- Subjects
- Animals, Contrast Media, Disease Models, Animal, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins genetics, Somatosensory Cortex drug effects, Synaptic Transmission drug effects, Treatment Outcome, Tubulin Modulators therapeutic use, Epothilones therapeutic use, Magnetic Resonance Imaging methods, Manganese pharmacokinetics, Microtubule-Associated Proteins metabolism, Schizophrenia drug therapy, Schizophrenia physiopathology, Somatosensory Cortex physiopathology
- Abstract
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., (Copyright © 2014. Published by Elsevier Inc.)
- Published
- 2014
- Full Text
- View/download PDF
24. Neuronal architectures with axo-dendritic polarity above silicon nanowires.
- Author
-
Roth S, Bugnicourt G, Bisbal M, Gory-Fauré S, Brocard J, and Villard C
- Subjects
- Animals, Axons ultrastructure, Cells, Cultured, Dendrites ultrastructure, Mice, Microscopy, Electron, Scanning, Nanotechnology methods, Neurons ultrastructure, Axons metabolism, Dendrites metabolism, Nanowires chemistry, Neurons metabolism, Silicon chemistry
- Abstract
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., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
- View/download PDF
25. How morphological constraints affect axonal polarity in mouse neurons.
- Author
-
Roth S, Bisbal M, Brocard J, Bugnicourt G, Saoudi Y, Andrieux A, Gory-Fauré S, and Villard C
- Subjects
- Animals, Cells, Cultured, Centrosome, Hippocampus cytology, Mice, Axons, Cell Polarity, Neurons cytology
- 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
- Full Text
- View/download PDF
26. Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.
- Author
-
Andrieux A, Salin P, Schweitzer A, Bégou M, Pachoud B, Brun P, Gory-Fauré S, Kujala P, Suaud-Chagny MF, Höfle G, and Job D
- Subjects
- Animals, Behavior, Animal physiology, Cells, Cultured, Disease Models, Animal, Electric Stimulation methods, Excitatory Postsynaptic Potentials drug effects, Exploratory Behavior drug effects, Female, Hippocampus pathology, Male, Maternal Behavior drug effects, Mice, Mice, Inbred BALB C, Mice, Knockout, Microtubule-Associated Proteins deficiency, Neuronal Plasticity drug effects, Neuronal Plasticity physiology, Neuronal Plasticity radiation effects, Synaptic Transmission physiology, Behavior, Animal drug effects, Epothilones administration & dosage, Neurons drug effects, Schizophrenia drug therapy, Schizophrenia pathology, Schizophrenia physiopathology, Synaptic Transmission drug effects, Tubulin Modulators administration & dosage
- Abstract
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
- Full Text
- View/download PDF
27. STOP-like protein 21 is a novel member of the STOP family, revealing a Golgi localization of STOP proteins.
- Author
-
Gory-Fauré S, Windscheid V, Bosc C, Peris L, Proietto D, Franck R, Denarier E, Job D, and Andrieux A
- Subjects
- Amino Acid Sequence, Animals, Calmodulin metabolism, HeLa Cells, Humans, Mice, Microtubule-Associated Proteins physiology, Microtubules metabolism, Molecular Sequence Data, NIH 3T3 Cells, Palmitic Acid metabolism, Synapses physiology, Golgi Apparatus chemistry, Microtubule-Associated Proteins analysis
- Abstract
Neuronal microtubules are stabilized by two calmodulin-regulated microtubule-associated proteins, E-STOP and N-STOP, which when suppressed in mice induce severe synaptic and behavioral deficits. Here we show that mature neurons also contain a 21-kDa STOP-like protein, SL21, which shares calmodulin-binding and microtubule-stabilizing homology domains with STOP proteins. Accordingly, in different biochemical or cellular assays, SL21 has calmodulin binding and microtubule stabilizing activity. However, in cultured hippocampal neurons, SL21 antibodies principally stain the somatic Golgi and punctate Golgi material in neurites. In cycling cells, transfected SL21 decorates microtubules when expressed at high levels but is otherwise principally visible at the Golgi. The Golgi targeting of SL21 depends on the presence of cysteine residues located within the SL21 N-terminal domain, suggesting that Golgi targeting may require SL21 palmitoylation. Accordingly we find that SL21 is palmitoylated in vivo. N-STOP and E-STOP, which contain the Golgi targeting sequences present in SL21, also display distinct Golgi staining when expressed at low level in cycling cells. Thus neuronal proteins of the STOP family have the capacity to associate with Golgi material, which could be important for STOP synaptic functions.
- Published
- 2006
- Full Text
- View/download PDF
28. Phosphorylation of microtubule-associated protein STOP by calmodulin kinase II.
- Author
-
Baratier J, Peris L, Brocard J, Gory-Fauré S, Dufour F, Bosc C, Fourest-Lieuvin A, Blanchoin L, Salin P, Job D, and Andrieux A
- Subjects
- Actins chemistry, Animals, Brain metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin metabolism, Hippocampus metabolism, Mice, Microscopy, Fluorescence, Neurons metabolism, Phosphorylation, Protein Transport, Synapses metabolism, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Microtubule-Associated Proteins metabolism, Microtubules metabolism
- 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
- Full Text
- View/download PDF
29. The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders.
- Author
-
Andrieux A, Salin PA, Vernet M, Kujala P, Baratier J, Gory-Fauré S, Bosc C, Pointu H, Proietto D, Schweitzer A, Denarier E, Klumperman J, and Job D
- Subjects
- Animals, Anti-Anxiety Agents pharmacology, Antipsychotic Agents pharmacology, Behavior, Animal drug effects, Brain pathology, Cold Temperature, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Knockout, Microscopy, Electron, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins physiology, Microtubules pathology, Microtubules physiology, Neuronal Plasticity, Synapses pathology, Synaptic Transmission, Behavior, Animal physiology, Brain physiopathology, Microtubule-Associated Proteins deficiency, Synapses physiology
- 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
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.