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

Abstract

The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1 -/y) has an epileptogenic phenotype that is triggered by group I metabo-tropic 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.