Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome

J Neurosci. 2015 Mar 4;35(9):3938-45. doi: 10.1523/JNEUROSCI.4499-14.2015. Epub 2015 Mar 4.

Abstract

The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1(-/y)) has an epileptogenic phenotype that is triggered by group I metabotropic glutamate receptor (mGluR) activation. We found that a membrane-permeable peptide that disrupts mGluR5 interactions with long-form Homers enhanced mGluR-induced epileptiform burst firing in wild-type (WT) animals, replicating the early stages of hyperexcitability in Fmr1(-/y). The peptide enhanced mGluR-evoked endocannabinoid (eCB)-mediated suppression of inhibitory synapses, decreased it at excitatory synapses in WTs, but had no effect on eCB actions in Fmr1(-/y). At a low concentration, the mGluR agonist did not generate eCBs at excitatory synapses but nevertheless induced burst firing in both Fmr1(-/y) and peptide-treated WT slices. This burst firing was suppressed by a cannabinoid receptor antagonist. We suggest that integrity of Homer scaffolds is essential for normal mGluR-eCB functioning and that aberrant eCB signaling resulting from disturbances of this molecular structure contributes to the epileptic phenotype of Fmr1(-/y).

Keywords: DHPG; Fmr1; epilepsy; hippocampus; inhibitory synapses; seizure.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Endocannabinoids / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / physiology
  • Fragile X Syndrome / metabolism*
  • Hippocampus / metabolism
  • Homer Scaffolding Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Carrier Proteins
  • Endocannabinoids
  • Fmr1 protein, mouse
  • Homer Scaffolding Proteins
  • Receptor, Cannabinoid, CB1
  • Receptor, Metabotropic Glutamate 5
  • Fragile X Mental Retardation Protein