학술논문
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
Document Type
Academic Journal
Author
Aloisi E; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Le Corf K; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Dupuis J; Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux, 33077, Bordeaux, cedex, France.; University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, cedex, France.; Zhang P; Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux, 33077, Bordeaux, cedex, France.; University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, cedex, France.; Ginger M; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Labrousse V; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux, 33077, Bordeaux, cedex, France.; University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, cedex, France.; Spatuzza M; Institute of Neurological Sciences, National Research Council, ISN-CNR, 95126, Catania, Italy.; Georg Haberl M; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Costa L; Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy.; Shigemoto R; IST Austria, Klosterneuburg, 3400, Austria.; Tappe-Theodor A; Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.; Drago F; Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.; Vincenzo Piazza P; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.; Mulle C; Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux, 33077, Bordeaux, cedex, France.; University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, cedex, France.; Groc L; Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux, 33077, Bordeaux, cedex, France.; University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, cedex, France.; Ciranna L; Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.; Catania MV; Institute of Neurological Sciences, National Research Council, ISN-CNR, 95126, Catania, Italy. mariavincenza.catania@cnr.it.; Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging (IRCCS), 94018, Troina (EN), Italy. mariavincenza.catania@cnr.it.; Frick A; INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France. andreas.frick@inserm.fr.; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, 33077, Bordeaux, cedex, France. andreas.frick@inserm.fr.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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.