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

Elisabetta Aloisi, Katy Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, Matthias Georg Haberl, Lara Costa, Ryuichi Shigemoto, Anke Tappe-Theodor, Filippo Drago, Pier Vincenzo Piazza, Christophe Mulle, Laurent Groc, Lucia Ciranna, Maria Vincenza Catania () and Andreas Frick ()
Additional contact information
Elisabetta Aloisi: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Katy Corf: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Julien Dupuis: Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
Pei Zhang: Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
Melanie Ginger: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Virginie Labrousse: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Michela Spatuzza: Institute of Neurological Sciences, National Research Council, ISN-CNR
Matthias Georg Haberl: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Lara Costa: University of Messina
Ryuichi Shigemoto: IST Austria
Anke Tappe-Theodor: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366
Filippo Drago: University of Catania
Pier Vincenzo Piazza: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
Christophe Mulle: Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
Laurent Groc: Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
Lucia Ciranna: University of Catania
Maria Vincenza Catania: Institute of Neurological Sciences, National Research Council, ISN-CNR
Andreas Frick: INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01191-2

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