Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice

Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the patho-physiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level,and related synaptic and cognitive phenotypes are unexplored. Here, we probed the con-sequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synapticN-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in thesecond-generationFmr1knockout (KO) mouse. Using single-molecule tracking, we found thatmGluR5 was significantly more mobile at synapses in hippocampalFmr1KO neurons, causingan increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with areduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-termdepression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic andbehavioral phenomena were reversed by knocking down Homer1a inFmr1KO mice. Our studyprovides a mechanistic link between changes of mGluR5 dynamics and pathologicalphenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.