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

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  • Elisabetta Aloisi

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

  • Katy Corf

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

  • Julien Dupuis

    (Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
    University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297)

  • Pei Zhang

    (Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
    University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297)

  • Melanie Ginger

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

  • Virginie Labrousse

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
    University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297)

  • Michela Spatuzza

    (Institute of Neurological Sciences, National Research Council, ISN-CNR)

  • Matthias Georg Haberl

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

  • Lara Costa

    (University of Messina)

  • Ryuichi Shigemoto

    (IST Austria)

  • Anke Tappe-Theodor

    (Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366)

  • Filippo Drago

    (University of Catania)

  • Pier Vincenzo Piazza

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

  • Christophe Mulle

    (Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
    University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297)

  • Laurent Groc

    (Interdisciplinary Institute for Neuroscience, IINS-CNRS, UMR 5297, University of Bordeaux
    University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297)

  • Lucia Ciranna

    (University of Catania)

  • Maria Vincenza Catania

    (Institute of Neurological Sciences, National Research Council, ISN-CNR
    Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging (IRCCS))

  • Andreas Frick

    (INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215
    University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215)

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.

Suggested Citation

  • Elisabetta Aloisi & Katy Corf & Julien Dupuis & Pei Zhang & Melanie Ginger & Virginie Labrousse & Michela Spatuzza & Matthias Georg Haberl & Lara Costa & Ryuichi Shigemoto & Anke Tappe-Theodor & Filip, 2017. "Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01191-2
    DOI: 10.1038/s41467-017-01191-2
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    Cited by:

    1. Danijela Bataveljic & Helena Pivonkova & Vidian de Concini & Betty Hébert & Pascal Ezan & Sylvain Briault & Alexis-Pierre Bemelmans & Jacques Pichon & Arnaud Menuet & Nathalie Rouach, 2024. "Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Nicky Scheefhals & Manon Westra & Harold D. MacGillavry, 2023. "mGluR5 is transiently confined in perisynaptic nanodomains to shape synaptic function," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Shun Li & Florian olde Heuvel & Rida Rehman & Oumayma Aousji & Albrecht Froehlich & Zhenghui Li & Rebecca Jark & Wanhong Zhang & Alison Conquest & Sarah Woelfle & Michael Schoen & Caitlin C. O´Meara &, 2023. "Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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