TY - JOUR
T1 - Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
AU - Aloisi, Elisabetta
AU - Le Corf, Katy
AU - Dupuis, Julien
AU - Zhang, Pei
AU - Ginger, Melanie
AU - Labrousse, Virginie
AU - Spatuzza, Michela
AU - Georg Haberl, Matthias
AU - Costa, Lara
AU - Shigemoto, Ryuichi
AU - Tappe-Theodor, Anke
AU - Drago, Filippo
AU - Vincenzo Piazza, Pier
AU - Mulle, Christophe
AU - Groc, Laurent
AU - Ciranna, Lucia
AU - Catania, Maria Vincenza
AU - Frick, Andreas
PY - 2017/10/24
Y1 - 2017/10/24
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/s41467-017-01191-2
DO - 10.1038/s41467-017-01191-2
M3 - Article
C2 - 29062097
VL - 8
SP - 1103
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -