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

• Verfasst von: Aloisi, Elisabetta [VerfasserIn]
• Verfasst von: Tappe-Theodor, Anke [VerfasserIn]
• Titel: Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
• Verf.angabe: 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
• E-Jahr: 2017
• Jahr: 24 October 2017
• Umfang: 14 S.
• Fussnoten: Gesehen am 03.05.2018
• Titel Quelle: Enthalten in: Nature Communications
• Ort Quelle: [London] : Nature Publishing Group UK, 2010
• Jahr Quelle: 2017
• Band/Heft Quelle: 8(2017) Artikel-Nummer 1103, 14 Seiten
• ISSN Quelle: 2041-1723
• DOI: doi:10.1038/s41467-017-01191-2
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Animals
• Sach-SW: Cognition
• Sach-SW: Disease Models, Animal
• Sach-SW: Female
• Sach-SW: Fragile X Mental Retardation Protein
• Sach-SW: Fragile X Syndrome
• Sach-SW: Hippocampus
• Sach-SW: Humans
• Sach-SW: Male
• Sach-SW: Mice
• Sach-SW: Mice, Inbred C57BL
• Sach-SW: Mice, Knockout
• Sach-SW: Neuronal Plasticity
• Sach-SW: Receptor, Metabotropic Glutamate 5
• Sach-SW: Receptors, N-Methyl-D-Aspartate
• Sach-SW: Synapses
• K10plus-PPN: 1572573236

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.