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

J Neurosci. 2015 Feb 18;35(7):3155-73. doi: 10.1523/JNEUROSCI.0586-14.2015.

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.

Keywords: ESCRT filaments; frontotemporal dementia; postsynaptic scaffold; spinoskeleton; structural plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Computer Simulation
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Endosomal Sorting Complexes Required for Transport / deficiency*
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Female
  • Hippocampus / cytology
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Immunoelectron
  • Mutation / genetics
  • N-Methylaspartate / pharmacology
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Neurons / cytology
  • Neurons / ultrastructure
  • Post-Synaptic Density / metabolism
  • Post-Synaptic Density / ultrastructure
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / physiology*
  • Synapses / ultrastructure

Substances

  • CHMP2B protein, mouse
  • Endosomal Sorting Complexes Required for Transport
  • Excitatory Amino Acid Agonists
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • red fluorescent protein
  • N-Methylaspartate