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

Dunot, Jade ; Moreno, Sebastien ; Gandin, Carine ; Pousinha, Paula A. ; Amici, Mascia ; Dupuis, Julien ; Anisimova, Margarita ; Winschel, Alex ; Uriot, Magalie ; Petshow, Samuel J. ; Mensch, Maria ; Bethus, Ingrid ; Giudici, Camilla ; Hampel, Heike ; Wefers, Benedikt ; Wurst, Wolfgang ; Naumann, Ronald ; Ashby, Michael C. ; Laube, Bodo ; Zito, Karen ; Mellor, Jack R. ; Groc, Laurent ; Willem, Michael ; Marie, Hélène (2024)
APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
In: Neuron, 112 (16)
doi: 10.1016/j.neuron.2024.05.027
Artikel, Bibliographie

Kurzbeschreibung (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.

Typ des Eintrags: Artikel
Erschienen: 2024
Autor(en): Dunot, Jade ; Moreno, Sebastien ; Gandin, Carine ; Pousinha, Paula A. ; Amici, Mascia ; Dupuis, Julien ; Anisimova, Margarita ; Winschel, Alex ; Uriot, Magalie ; Petshow, Samuel J. ; Mensch, Maria ; Bethus, Ingrid ; Giudici, Camilla ; Hampel, Heike ; Wefers, Benedikt ; Wurst, Wolfgang ; Naumann, Ronald ; Ashby, Michael C. ; Laube, Bodo ; Zito, Karen ; Mellor, Jack R. ; Groc, Laurent ; Willem, Michael ; Marie, Hélène
Art des Eintrags: Bibliographie
Titel: APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors
Sprache: Englisch
Publikationsjahr: 7 Juni 2024
Verlag: Cell Press
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Neuron
Jahrgang/Volume einer Zeitschrift: 112
(Heft-)Nummer: 16
DOI: 10.1016/j.neuron.2024.05.027
Kurzbeschreibung (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.

ID-Nummer: pmid:38878768
Fachbereich(e)/-gebiet(e): 10 Fachbereich Biologie
10 Fachbereich Biologie > Neurophysiologie und neurosensorische Systeme
Hinterlegungsdatum: 17 Jun 2024 11:53
Letzte Änderung: 26 Aug 2024 11:55
PPN: 51919182X
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