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

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Veröffentlicht in:	Nature Communications 8(2017) Artikel-Nummer 1103, 14 Seiten
Personen und Körperschaften:	Aloisi, Elisabetta (VerfasserIn), Tappe-Theodor, Anke (VerfasserIn)
Titel:	Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice/ Elisabetta Aloisi, Katy Le 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 & Andreas Frick
Format:	E-Book-Kapitel
Sprache:	Englisch
veröffentlicht:	24 October 2017
Gesamtaufnahme:	: Nature Communications, 8(2017) Artikel-Nummer 1103, 14 Seiten , volume:8
Schlagwörter:	Animals Cognition Disease Models, Animal Female Fragile X Mental Retardation Protein Fragile X Syndrome Hippocampus Humans Male Mice Mice, Inbred C57BL Mice, Knockout Neuronal Plasticity Receptor, Metabotropic Glutamate 5 Receptors, N-Methyl-D-Aspartate Synapses
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Zusammenfassung:	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.
Beschreibung:	Gesehen am 03.05.2018
Umfang:	14
ISSN:	2041-1723
DOI:	10.1038/s41467-017-01191-2