PMID- 29062097
OWN - NLM
STAT- MEDLINE
DCOM- 20180427
LR  - 20181113
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Oct 24
TI  - Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive 
      defects in Fmr1 knockout mice.
PG  - 1103
LID - 10.1038/s41467-017-01191-2 [doi]
LID - 1103
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.
FAU - Aloisi, Elisabetta
AU  - Aloisi E
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
FAU - Le Corf, Katy
AU  - Le Corf K
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
FAU - Dupuis, Julien
AU  - Dupuis J
AD  - Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of 
      Bordeaux, 33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 
      33077, Bordeaux, cedex, France.
FAU - Zhang, Pei
AU  - Zhang P
AD  - Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of 
      Bordeaux, 33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 
      33077, Bordeaux, cedex, France.
FAU - Ginger, Melanie
AU  - Ginger M
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
FAU - Labrousse, Virginie
AU  - Labrousse V
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
AD  - Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of 
      Bordeaux, 33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 
      33077, Bordeaux, cedex, France.
FAU - Spatuzza, Michela
AU  - Spatuzza M
AD  - Institute of Neurological Sciences, National Research Council, ISN-CNR, 95126, 
      Catania, Italy.
FAU - Georg Haberl, Matthias
AU  - Georg Haberl M
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
FAU - Costa, Lara
AU  - Costa L
AUID- ORCID: 0000-0002-2465-8080
AD  - Department of Clinical and Experimental Medicine, University of Messina, 98125, 
      Messina, Italy.
FAU - Shigemoto, Ryuichi
AU  - Shigemoto R
AD  - IST Austria, Klosterneuburg, 3400, Austria.
FAU - Tappe-Theodor, Anke
AU  - Tappe-Theodor A
AD  - Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 
      69120, Heidelberg, Germany.
FAU - Drago, Filippo
AU  - Drago F
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      95123, Catania, Italy.
FAU - Vincenzo Piazza, Pier
AU  - Vincenzo Piazza P
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France.
FAU - Mulle, Christophe
AU  - Mulle C
AD  - Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of 
      Bordeaux, 33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 
      33077, Bordeaux, cedex, France.
FAU - Groc, Laurent
AU  - Groc L
AD  - Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of 
      Bordeaux, 33077, Bordeaux, cedex, France.
AD  - University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 
      33077, Bordeaux, cedex, France.
FAU - Ciranna, Lucia
AU  - Ciranna L
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      95123, Catania, Italy.
FAU - Catania, Maria Vincenza
AU  - Catania MV
AD  - Institute of Neurological Sciences, National Research Council, ISN-CNR, 95126, 
      Catania, Italy. mariavincenza.catania@cnr.it.
AD  - Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging 
      (IRCCS), 94018, Troina (EN), Italy. mariavincenza.catania@cnr.it.
FAU - Frick, Andreas
AU  - Frick A
AD  - INSERM, Neurocentre Magendie, Physiopathologie de la plasticite neuronale, U1215, 
      33077, Bordeaux, cedex, France. andreas.frick@inserm.fr.
AD  - University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticite 
      neuronale, U1215, 33077, Bordeaux, cedex, France. andreas.frick@inserm.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171024
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Fmr1 protein, mouse)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
SB  - IM
MH  - Animals
MH  - Cognition
MH  - Disease Models, Animal
MH  - Female
MH  - Fragile X Mental Retardation Protein/*genetics/metabolism
MH  - Fragile X Syndrome/genetics/*metabolism/*psychology
MH  - Hippocampus/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuronal Plasticity
MH  - Receptor, Metabotropic Glutamate 5/genetics/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism
MH  - Synapses/genetics/*metabolism
PMC - PMC5653653
COIS- The authors declare no competing financial interests
EDAT- 2017/10/25 06:00
MHDA- 2018/04/28 06:00
PMCR- 2017/10/24
CRDT- 2017/10/25 06:00
PHST- 2016/04/22 00:00 [received]
PHST- 2017/08/24 00:00 [accepted]
PHST- 2017/10/25 06:00 [entrez]
PHST- 2017/10/25 06:00 [pubmed]
PHST- 2018/04/28 06:00 [medline]
PHST- 2017/10/24 00:00 [pmc-release]
AID - 10.1038/s41467-017-01191-2 [pii]
AID - 1191 [pii]
AID - 10.1038/s41467-017-01191-2 [doi]
PST - epublish
SO  - Nat Commun. 2017 Oct 24;8(1):1103. doi: 10.1038/s41467-017-01191-2.