Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
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Author
Aloisi, Elisabetta;
Le Corf, Katy;
Dupuis, Julien;
Zhang, Pei;
Ginger, Melanie;
Labrousse, Virginie;
Spatuzza, Michela;
Georg Haberl, Matthias;
Costa, Lara;
Shigemoto, RyuichiISTA
;
Tappe Theodor, Anke;
Drago, Fillippo
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All
Department
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.
Publishing Year
Date Published
2017-12-01
Journal Title
Nature Communications
Publisher
Nature Publishing Group
Volume
8
Issue
1
Article Number
1103
ISSN
IST-REx-ID
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