APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors
Neuron. 2024-06-01; :
DOI: 10.1016/j.neuron.2024.05.027
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Dunot J(1), Moreno S(2), Gandin C(2), Pousinha PA(2), Amici M(3), Dupuis J(4),
Anisimova M(5), Winschel A(6), Uriot M(4), Petshow SJ(5), Mensch M(2), Bethus
I(2), Giudici C(7), Hampel H(8), Wefers B(9), Wurst W(10), Naumann R(11), Ashby
MC(3), Laube B(6), Zito K(5), Mellor JR(3), Groc L(4), Willem M(12), Marie
H(13).
Author information:
(1)Université Côte d’Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire
et Cellulaire, 06560 Valbonne, France; Munich Cluster for Systems Neurology
(SyNergy), 81377 Munich, Germany.
(2)Université Côte d’Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire
et Cellulaire, 06560 Valbonne, France.
(3)Centre for Synaptic Plasticity, School of Physiology, Pharmacology and
Neuroscience, University of Bristol, Bristol BS8 1TD, UK.
(4)Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience,
33076 Bordeaux Cedex, France.
(5)Center for Neuroscience, University of California, Davis, Davis, CA 95618,
USA.
(6)Department of Biology, Neurophysiology und Neurosensory Systems, TU
Darmstadt, 64287 Darmstadt, Germany.
(7)German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich,
Germany.
(8)Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of
Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
(9)German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich,
Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, 85764
Neuherberg, Germany.
(10)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.
(11)Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden,
Germany.
(12)Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of
Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Electronic address: .
(13)Université Côte d’Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire
et Cellulaire, 06560 Valbonne, France. Electronic address: .
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.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neuron.2024.05.027
PMID: 38878768
Conflict of interest statement: Declaration of interests The authors declare no
competing interests.