Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein
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.
Reviewing Editor
- Inna Slutsky, Tel Aviv University, Israel
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.
Version history
- Received: February 2, 2017
- Accepted: July 5, 2017
- Accepted Manuscript published: July 6, 2017 (version 1)
- Accepted Manuscript updated: July 7, 2017 (version 2)
- 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
-
- 2,227
- views
-
- 472
- downloads
-
- 24
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Neuroscience
Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.
-
- Neuroscience
Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.