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

E. Aloisi, K. Le Corf, J. Dupuis, P. Zhang, M. Ginger, V. Labrousse, M. Spatuzza, M. Georg Haberl, L. Costa, R. Shigemoto, A. Tappe Theodor, F. Drago, P. Vincenzo Piazza, C. Mulle, L. Groc, L. Ciranna, M. Catania, A. Frick, Nature Communications 8 (2017).

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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
Volume
8
Issue
1
Article Number
1103
ISSN
IST-REx-ID

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Aloisi E, Le Corf K, Dupuis J, et al. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications. 2017;8(1). doi:10.1038/s41467-017-01191-2
Aloisi, E., Le Corf, K., Dupuis, J., Zhang, P., Ginger, M., Labrousse, V., … Frick, A. (2017). Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications, 8(1). https://doi.org/10.1038/s41467-017-01191-2
Aloisi, Elisabetta, Katy Le Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, et al. “Altered Surface MGluR5 Dynamics Provoke Synaptic NMDAR Dysfunction and Cognitive Defects in Fmr1 Knockout Mice.” Nature Communications 8, no. 1 (2017). https://doi.org/10.1038/s41467-017-01191-2.
E. Aloisi et al., “Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice,” Nature Communications, vol. 8, no. 1, 2017.
Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, Spatuzza M, Georg Haberl M, Costa L, Shigemoto R, Tappe Theodor A, Drago F, Vincenzo Piazza P, Mulle C, Groc L, Ciranna L, Catania M, Frick A. 2017. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications. 8(1).
Aloisi, Elisabetta, et al. “Altered Surface MGluR5 Dynamics Provoke Synaptic NMDAR Dysfunction and Cognitive Defects in Fmr1 Knockout Mice.” Nature Communications, vol. 8, no. 1, 1103, Nature Publishing Group, 2017, doi:10.1038/s41467-017-01191-2.
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