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Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology 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 consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.
Pubmed ID: 29062097 RIS Download
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View all literature mentionsA sweep-based data acquisition and analysis software package. Its uses range from a simple storage oscilloscope to complex applications requiring stimulus generation, data capture, control of external equipment and custom analysis. A built-in script language automates tasks and provides additional tools for custom analyses and applications. Signal includes functions for specific application areas, including dynamic clamp, whole cell and patch clamp electrophysiology, and evoked response including control of magnetic and other stimulus devices. Video tutorials and a demo version of Signal is available on the main page.
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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