title: Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B.
abstract: The charged multivesicular body proteins (Chmp1-7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: Romain
authors.identifier: http://orcid.org/0000-0001-9608-4189
authors.initials: R
authors.lastname: Chassefeyre
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-Hernández
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France, Universités de Montpellier 1 & 2, UMR-5203, F-34094 Montpellier, France, INSERM, Unité 661, F-34094 Montpellier, France.
authors.forename: Federica
authors.initials: F
authors.lastname: Bertaso
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France, Universités de Montpellier 1 & 2, UMR-5203, F-34094 Montpellier, France, INSERM, Unité 661, F-34094 Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouquier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Blot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Laporte
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Fraboulet
authors.affiliation: INSERM, Unité 1038, F-38054 Grenoble, France, Commissariat à l'Energie Atomique (CEA), Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV), Laboratoire de Biologie à Grande Echelle, F-38054 Grenoble, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Couté
authors.affiliation: Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.affiliation: Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Pernet-Gallay
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France, yves.goldberg@ujf-grenoble.fr remy.sadoul@ujf-grenoble.fr.
authors.forename: Rémy
authors.initials: R
authors.lastname: Sadoul
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France, Universités de Montpellier 1 & 2, UMR-5203, F-34094 Montpellier, France, INSERM, Unité 661, F-34094 Montpellier, France.
authors.forename: Laurent
authors.identifier: http://orcid.org/0000-0002-7695-7832
authors.initials: L
authors.lastname: Fagni
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 836, F-38042 Grenoble, France, Université Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France, CEA, iRTSV, Groupe Physiopathologie du Cytosquelette (GPC), F-38054 Grenoble, France yves.goldberg@ujf-grenoble.fr remy.sadoul@ujf-grenoble.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D056827:Endosomal Sorting Complexes Required for Transport / Q000172:deficiency* / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000648:ultrastructure; D057907:Post-Synaptic Density / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D000097573:Red Fluorescent Protein
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D018690:Excitatory Amino Acid Agonists; D008164:Luminescent Proteins; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D000097573:Red Fluorescent Protein; C525139:CHMP2B protein, mouse
keywords: ESCRT filaments; frontotemporal dementia; postsynaptic scaffold; spinoskeleton; structural plasticity