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

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

doi:10.1523/JNEUROSCI.0586-14.2015

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

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^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3155-3173
Number of pages	19
Journal	Journal of Neuroscience
Volume	35
Issue number	7
DOIs	https://doi.org/10.1523/JNEUROSCI.0586-14.2015
Publication status	Published - 18 Feb 2015

Keywords

ESCRT filaments
Frontotemporal dementia
Postsynaptic scaffold
Spinoskeleton
Structural plasticity

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10.1523/JNEUROSCI.0586-14.2015

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Chassefeyre, R., Martínez-Hernández, J., Bertaso, F., Bouquier, N., Blot, B., Laporte, M., Fraboulet, S., Couté, Y., Devoy, A., Isaacs, A. M., Pernet-Gallay, K., Sadoul, R., Fagni, L., & Goldberg, Y. (2015). Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B. Journal of Neuroscience, 35(7), 3155-3173. https://doi.org/10.1523/JNEUROSCI.0586-14.2015

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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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Chassefeyre, R, Martínez-Hernández, J, Bertaso, F, Bouquier, N, Blot, B, Laporte, M, Fraboulet, S, Couté, Y, Devoy, A, Isaacs, AM, Pernet-Gallay, K, Sadoul, R, Fagni, L & Goldberg, Y 2015, 'Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B', Journal of Neuroscience, vol. 35, no. 7, pp. 3155-3173. https://doi.org/10.1523/JNEUROSCI.0586-14.2015

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T1 - Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B

AU - Chassefeyre, Romain

AU - Martínez-Hernández, José

AU - Bertaso, Federica

AU - Bouquier, Nathalie

AU - Blot, Béatrice

AU - Laporte, Marine

AU - Fraboulet, Sandrine

AU - Couté, Yohann

AU - Devoy, Anny

AU - Isaacs, Adrian M.

AU - Pernet-Gallay, Karin

AU - Sadoul, Rémy

AU - Fagni, Laurent

AU - Goldberg, Yves

PY - 2015/2/18

Y1 - 2015/2/18

N2 - 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.

AB - 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.

KW - ESCRT filaments

KW - Frontotemporal dementia

KW - Postsynaptic scaffold

KW - Spinoskeleton

KW - Structural plasticity

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M3 - Article

C2 - 25698751

AN - SCOPUS:84923021231

SN - 0270-6474

VL - 35

SP - 3155

EP - 3173

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 7

ER -

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

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Keywords

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