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

Autor:	Dunot J; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany., Moreno S; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France., Gandin C; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France., Pousinha PA; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France., Amici M; Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK., Dupuis J; Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, 33076 Bordeaux Cedex, France., Anisimova M; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA., Winschel A; Department of Biology, Neurophysiology und Neurosensory Systems, TU Darmstadt, 64287 Darmstadt, Germany., Uriot M; Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, 33076 Bordeaux Cedex, France., Petshow SJ; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA., Mensch M; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France., Bethus I; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France., Giudici C; German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany., Hampel H; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany., Wefers B; German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Wurst W; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Naumann R; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany., Ashby MC; Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK., Laube B; Department of Biology, Neurophysiology und Neurosensory Systems, TU Darmstadt, 64287 Darmstadt, Germany., Zito K; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA., Mellor JR; Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK., Groc L; Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, 33076 Bordeaux Cedex, France., Willem M; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: mwillem@med.uni-muenchen.de., Marie H; Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France. Electronic address: marie@ipmc.cnrs.fr.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Aug 21; Vol. 112 (16), pp. 2708-2720.e9. Date of Electronic Publication: 2024 Jun 14.
DOI:	10.1016/j.neuron.2024.05.027
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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