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Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B

Research output: Contribution to journalArticle

Romain Chassefeyre, José Martínez-Hernández, Federica Bertaso, Nathalie Bouquier, Béatrice Blot, Marine Laporte, Sandrine Fraboulet, Yohann Couté, Anny Devoy, Adrian M. Isaacs, Karin Pernet-Gallay, Rémy Sadoul, Laurent Fagni, Yves Goldberg

Original languageEnglish
Pages (from-to)3155-3173
Number of pages19
JournalJournal of Neuroscience
Volume35
Issue number7
DOIs
Published18 Feb 2015

King's Authors

Abstract

The charged multivesicular body proteins (Chmp1-7) are an evolutionary conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause fronto-temporal 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.

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