Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein
- Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, France
- Ludwig-Maximilians-University Munich, Germany
- 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.
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Author details
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.
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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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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