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.
Article and author information
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.
Metrics
-
- 2,340
- views
-
- 492
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
-
- Neuroscience
Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system (CNS) have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila CNS and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell-type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.
-
- Neuroscience
Cell identification is an important yet difficult process in data analysis of biological images. Previously, we developed an automated cell identification method called CRF_ID and demonstrated its high performance in Caenorhabditis elegans whole-brain images (Chaudhary et al., 2021). However, because the method was optimized for whole-brain imaging, comparable performance could not be guaranteed for application in commonly used C. elegans multi-cell images that display a subpopulation of cells. Here, we present an advancement, CRF_ID 2.0, that expands the generalizability of the method to multi-cell imaging beyond whole-brain imaging. To illustrate the application of the advance, we show the characterization of CRF_ID 2.0 in multi-cell imaging and cell-specific gene expression analysis in C. elegans. This work demonstrates that high-accuracy automated cell annotation in multi-cell imaging can expedite cell identification and reduce its subjectivity in C. elegans and potentially other biological images of various origins.
