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

• Published in: The Journal of neuroscience 2015-03, Vol.35 (9), p.3938-3945
• Main Authors: Tang, Ai-Hui, Alger, Bradley E
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4499-14.2015

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).