Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome.
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).
Department of Physiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201 tangaihui@gmail.com.
Ai-Hui
http://orcid.org/0000-0003-1641-8287
AH
Tang
Department of Physiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Bradley E
BE
Alger
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology; D005600:Fragile X Syndrome / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D002352:Carrier Proteins; D063388:Endocannabinoids; D051860:Fragile X Messenger Ribonucleoprotein 1; D000072233:Homer Scaffolding Proteins; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse
DHPG; Fmr1; epilepsy; hippocampus; inhibitory synapses; seizure