A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain

Neuron. 2015 May 6;86(3):726-39. doi: 10.1016/j.neuron.2015.03.049. Epub 2015 Apr 23.

Abstract

Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms a complex with endogenous FMRP, and knockout of Cdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anisomycin / pharmacology
  • Cdh1 Proteins / genetics
  • Cdh1 Proteins / metabolism*
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice, Transgenic
  • Protein Synthesis Inhibitors / pharmacology
  • Receptors, Metabotropic Glutamate / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Subcellular Fractions / metabolism
  • Synapses / genetics
  • Synapses / physiology*
  • Ubiquitin / metabolism

Substances

  • Cdh1 Proteins
  • Fmr1 protein, mouse
  • Fzr1 protein, mouse
  • Protein Synthesis Inhibitors
  • Receptors, Metabotropic Glutamate
  • Ubiquitin
  • Fragile X Mental Retardation Protein
  • Methoxyhydroxyphenylglycol
  • Anisomycin
  • 3,4-dihydroxyphenylglycol