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
Nat Commun. 2017-10-24; 8(1):
DOI: 10.1038/s41467-017-01191-2

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Aloisi E(1)(2), Le Corf K(1)(2), Dupuis J(3)(4), Zhang P(3)(4), Ginger M(1)(2), Labrousse V(1)(2)(3)(4), Spatuzza M(5), Georg Haberl M(1)(2), Costa L(6), Shigemoto R(7), Tappe-Theodor A(8), Drago F(9), Vincenzo Piazza P(1)(2), Mulle
C(3)(4), Groc L(3)(4), Ciranna L(9), Catania MV(10)(11), Frick A(12)(13).

Author information:
(1)INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale,
U1215, 33077, Bordeaux, cedex, France.
(2)University of Bordeaux, Neurocentre Magendie, Physiopathologie de la
plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.
(3)Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University
of Bordeaux, 33077, Bordeaux, cedex, France.
(4)University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, 33077, Bordeaux, cedex, France.
(5)Institute of Neurological Sciences, National Research Council, ISN-CNR, 95126,
Catania, Italy.
(6)Department of Clinical and Experimental Medicine, University of Messina,
98125, Messina, Italy.
(7)IST Austria, Klosterneuburg, 3400, Austria.
(8)Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366,
69120, Heidelberg, Germany.
(9)Department of Biomedical and Biotechnological Sciences, University of Catania,
95123, Catania, Italy.
(10)Institute of Neurological Sciences, National Research Council, ISN-CNR,
95126, Catania, Italy. .
(11)Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging
(IRCCS), 94018, Troina (EN), Italy. .
(12)INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale,
U1215, 33077, Bordeaux, cedex, France. .
(13)University of Bordeaux, Neurocentre Magendie, Physiopathologie de la
plasticité neuronale, U1215, 33077, Bordeaux, cedex, France.

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.

 

Auteurs Bordeaux Neurocampus