Journal Article

DZNE-2024-01065

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.

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

2024
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.neuron.2024.05.027

Abstract: 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.

Keyword(s): Humans (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Signal Transduction: physiology (MeSH) ; Long-Term Synaptic Depression: physiology (MeSH) ; Long-Term Synaptic Depression: drug effects (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Fear: physiology (MeSH) ; Hippocampus: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Dendritic Spines: metabolism (MeSH) ; Memory: physiology (MeSH) ; Rats (MeSH) ; APP ; NMDA receptors ; amyloid-β precursor protein ; eta-secretase ; hippocampus ; long-term depression ; memory ; non-ionotropic signaling ; spine shrinkage ; synapse ; Receptors, N-Methyl-D-Aspartate ; Amyloid beta-Protein Precursor

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)
2. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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