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, Boradeaux, 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.

Metrics

  • 2,020
    Page views
  • 438
    Downloads
  • 16
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine
    Bilal Cakir, In-Hyun Park
    Insight

    Fusing brain organoids with blood vessel organoids leads to the incorporation of non-neural endothelial cells and microglia into the brain organoids.

    1. Neuroscience
    Aoi Ichiyama et al.
    Research Article

    The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to elevated emergency response. However, neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRHPVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long (~2 s) inter-burst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRHPVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing a direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRHPVN neurons.