Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome

This study shows that the interaction between metabotropic glutamate receptor 5 (mGluR5) and a specific form of the scaffolding protein Homer contributes to the behavioral and physiological defects in the mouse model of fragile X syndrome. Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model, Fmr1 knockout ( Fmr1 −/ y ). In Fmr1 −/ y mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5–long Homer scaffolds and corrected several phenotypes in Fmr1 −/ y mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many Fmr1 −/ y phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of Fmr1 . Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.