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

Author(s): Aloisi, Elisabetta; Le Corf, Katy; Dupuis, Julien P; Zhang, Pei; Ginger, Melanie; Labrousse, Virginie F; Spatuzza, Michela; Georg Haberl, Matthias; Costa, Lara; Shigemoto, Ryuichi; Tappe-Theodor, Anke; Drago, Fillippo; Vincenzo Piazza, Pier; Mulle, Christophe; Groc, Laurent; Ciranna, Lucia; Catania, Maria Vincenza; Frick, Andreas
Article Title: Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
Affiliation IST Austria
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.
Journal Title: Nature Communications
Volume: 8
Issue 1
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2017-12-01
Start Page: Article number: 1103
Copyright Statement: CC BY 4.0
DOI: 10.1038/s41467-017-01191-2
Notes: We thank Silvia Viana da Silva, Arnau Busquets Garcia, Laurent Ladépêche, Jennifer Peterson, Shaam Al Abed and Guillaume Bony for constructive discussions and scientific advice. We thank the team of Daniel Choquet for initial help with the method of quantum dot imaging and its analysis. We also thank Nathalie Sans and Mireille Montcouquiol for use of their culture room, and Giovanni Marsicano and Aline Marighetto (all Neurocentre Magendie, Bordeaux) for use of their behavior equipment. We thank Isabel del Pino for support with confocal imaging, and Susanna Pietropaolo for advice on behavioral experiments. We thank Carmela M. Bonaccorso and Giuseppina Barrancotto (both Oasi Maria SS, Troina) for genotyping of the Fmr1 KO mice for electrophysiological experiments performed at University of Catania, the genotyping facility of the Neurocentre Magendie for all other genotyping services. Some data were acquired using equipment of the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University. This research was supported by the International PhD Program in Neuroscience from the University of Catania (Italy), Telethon (GGP07264), Oasi Maria SS Troina (“Ricerca Finalizzata—PE-2013-02355126 of the Italian Ministry of Health), INSERM, Labex-BRAIN (ANR-10-LABEX-43), Conseil de la Region d’Aquitaine, Fondation Jérôme Lejeune, Fédération pour la Recherche sur le Cerveau, Fondation pour la Recherche Médicale (ING20140129376) and Erasmus Mundus/ENC-Network.
Open access: yes (OA journal)