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
-
- 2,326
- views
-
- 490
- downloads
-
- 27
- 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
Sound location coding has been extensively studied at the central nucleus of the mammalian inferior colliculus (CNIC), supporting a population code. However, this population code has not been extensively characterized on the single-trial level with simultaneous recordings or at other anatomical regions like the dorsal cortex of inferior colliculus (DCIC), which is relevant for learning-induced experience dependent plasticity. To address these knowledge gaps, here we made in two complementary ways large-scale recordings of DCIC populations from awake mice in response to sounds delivered from 13 different frontal horizontal locations (azimuths): volumetric two-photon calcium imaging with ~700 cells simultaneously recorded at a relatively low temporal resolution, and high-density single-unit extracellular recordings with ~20 cells simultaneously recorded at a high temporal resolution. Independent of the method, the recorded DCIC population responses revealed substantial trial-to-trial variation (neuronal noise) which was significantly correlated across pairs of neurons (noise correlations) in the passively listening condition. Nevertheless, decoding analysis supported that these noisy response patterns encode sound location on the single-trial basis, reaching errors that match the discrimination ability of mice. The detected noise correlations contributed to minimize the error of the DCIC population code of sound azimuth. Altogether these findings point out that DCIC can encode sound location in a similar format to what has been proposed for CNIC, opening exciting questions about how noise correlations could shape this code in the context of cortico-collicular input and experience-dependent plasticity.
-
- Neuroscience
The alpha-synuclein (αSyn) seeding amplification assay (SAA) that allows the generation of disease-specific in vitro seeded fibrils (SAA fibrils) is used as a research tool to study the connection between the structure of αSyn fibrils, cellular seeding/spreading, and the clinicopathological manifestations of different synucleinopathies. However, structural differences between human brain-derived and SAA αSyn fibrils have been recently highlighted. Here, we characterize the biophysical properties of the human brain-derived αSyn fibrils from the brains of patients with Parkinson’s disease with and without dementia (PD, PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and compare them to the ‘model’ SAA fibrils. We report that the brain-derived αSyn fibrils show distinct biochemical profiles, which were not replicated in the corresponding SAA fibrils. Furthermore, the brain-derived αSyn fibrils from all synucleinopathies displayed a mixture of ‘straight’ and ‘twisted’ microscopic structures. However, the PD, PDD, and DLB SAA fibrils had a ’straight’ structure, whereas MSA SAA fibrils showed a ‘twisted’ structure. Finally, the brain-derived αSyn fibrils from all four synucleinopathies were phosphorylated (S129). Interestingly, phosphorylated αSyn were carried over to the PDD and DLB SAA fibrils. Our findings demonstrate the limitation of the SAA fibrils modeling the brain-derived αSyn fibrils and pay attention to the necessity of deepening the understanding of the SAA fibrillation methodology.
