Abstract
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.
Highlights
Metabotropic glutamate receptor subtype 5 is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored
Exaggerated group-I metabotropic glutamate receptor subtype 5/ protein synthesis-dependent hippocampal long-term depression (LTD) of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) currents is a hallmark feature of FXS13
These changes are accompanied by an enhanced co-clustering of Metabotropic glutamate receptor subtype 5 (mGluR5) and NMDA receptor (NMDAR) at synapses as well as altered NMDAR function/plasticity in the hippocampal CA1 region of Fmr[1] KO mice
Summary
Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr[1] 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. Exaggerated group-I metabotropic glutamate receptor subtype 5 (mGluR5)/ protein synthesis-dependent hippocampal long-term depression (LTD) of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) currents is a hallmark feature of FXS13. This seminal finding forms the basis of the mGluR theory of FXS14. In the presence of Homer1a, the multimeric mGluR5/Homer complex is disrupted, permitting direct physical and functional interactions between NMDAR and mGluR5 and promoting mGluR5-mediated inhibition of NMDAR currents[30, 31]
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