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Dunot, J.* ; Moreno, S.G.* ; Gandin, C.* ; Pousinha, P.A.* ; Amici, M.* ; Dupuis, J.* ; Anisimova, M.* ; Winschel, A.* ; Uriot, M.* ; Petshow, S.J.* ; Mensch, M.* ; Bethus, I.* ; Giudici, C.* ; Hampel, H.* ; Wefers, B. ; Wurst, W. ; Naumann, R.* ; Ashby, M.C.* ; Laube, B.* ; Zito, K.* ; Mellor, J.R.* ; Groc, L.* ; Willem, M.* ; Marie, H.*

APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.

Neuron 112, 2708-2720.e9 (2024)
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NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.
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Publication type Article: Journal article
Document type Scientific Article
Keywords App ; Nmda Receptors ; Amyloid-β Precursor Protein ; Eta-secretase ; Hippocampus ; Long-term Depression ; Memory ; Non-ionotropic Signaling ; Spine Shrinkage ; Synapse; Synaptic Plasticity; Allosteric Modulation; Silent Synapses; Variants; Disease
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0896-6273
e-ISSN 1097-4199
Journal Neuron
Quellenangaben Volume: 112, Issue: 16, Pages: 2708-2720.e9 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
Grants Ministe re de la Recherche, de l'Enseignement Superieur et de l'Innovation
French Association France Alzheimer
French Fondation Alzheimer
Agence Nationale de la Recherche
Flag ERA JTC
Investments for the Future LABEX SIG-NALIFE
Fondation pour la Recherche Medicale (FRM)
European Research Council
Institut Neuromod, Universite Cote d'Azur
MRC
EUFP17 Marie Curie Actions
Wellcome Trust
BBSRC
NIH
Deutsche Forschungsgemeinschaft Walter Benjamin project
Centre National de la Recherche Scientifique (CNRS)
DOI 10.1016/j.neuron.2024.05.027
WOS ID 001300289000001
Scopus ID 85197044712
PubMed ID 38878768
Erfassungsdatum 2024-06-18
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