Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein

  1. Paula A Pousinha  Is a corresponding author
  2. Xavier Mouska
  3. Elisabeth F Raymond
  4. Carole Gwizdek
  5. Ghien Dhib
  6. Gwenola Poupon-Silvestre
  7. Laure-Emmanuelle Zaragosi
  8. Camilla Giudici
  9. Ingrid Bethus
  10. Emilie Pacary
  11. Michael Willem
  12. Hélène Marie  Is a corresponding author
  1. Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, France
  2. Ludwig-Maximilians-University Munich, Germany
  3. INSERM U1215, Neurocentre Magendie, France

Abstract

The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer’s disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in-vivo AICD expression, ex-vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.

Article and author information

Author details

  1. Paula A Pousinha

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    For correspondence
    pousinha@ipmc.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5992-9418
  2. Xavier Mouska

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4263-543X
  3. Elisabeth F Raymond

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Carole Gwizdek

    Team SUMOylation in neuronal function and dysfunction, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Ghien Dhib

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Gwenola Poupon-Silvestre

    Team SUMOylation in neuronal function and dysfunction, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Laure-Emmanuelle Zaragosi

    Team Physiological genomics of the eukaryotes, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Camilla Giudici

    Ludwig-Maximilians-University Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Ingrid Bethus

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Emilie Pacary

    INSERM U1215, Neurocentre Magendie, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael Willem

    Ludwig-Maximilians-University Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Hélène Marie

    Team Molecular Mechanisms of neuronal plasticity in health and disease, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France
    For correspondence
    marie@ipmc.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.

Funding

Centre National de la Recherche Scientifique

  • Paula A Pousinha
  • Carole Gwizdek
  • Ghien Dhib

Fondation pour la Recherche Médicale (SPF20130526736)

  • Paula A Pousinha

Fondation Plan Alzheimer (Senior Innovative Grant 2010)

  • Xavier Mouska
  • Elisabeth F Raymond
  • Hélène Marie

Canceropôle PACA

  • Laure-Emmanuelle Zaragosi

Agence Nationale de la Recherche (ANR-10-INBS-09-03 ANR-10-INBS-09-02)

  • Xavier Mouska
  • Laure-Emmanuelle Zaragosi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were done according to policies on the care and use of laboratory animals of European Communities Council Directive (2010/63). The protocols we approved by the French Research Ministry following evaluation by a specialized ethics committee (protocol number 00973.02). All efforts were made to minimize animal suffering and reduce the number of animals used.

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Publication history

  1. Received: February 2, 2017
  2. Accepted: July 5, 2017
  3. Accepted Manuscript published: July 6, 2017 (version 1)
  4. Accepted Manuscript updated: July 7, 2017 (version 2)
  5. Version of Record published: August 4, 2017 (version 3)

Copyright

© 2017, Pousinha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Paula A Pousinha
  2. Xavier Mouska
  3. Elisabeth F Raymond
  4. Carole Gwizdek
  5. Ghien Dhib
  6. Gwenola Poupon-Silvestre
  7. Laure-Emmanuelle Zaragosi
  8. Camilla Giudici
  9. Ingrid Bethus
  10. Emilie Pacary
  11. Michael Willem
  12. Hélène Marie
(2017)
Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein
eLife 6:e25659.
https://doi.org/10.7554/eLife.25659

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