1. APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
- Author
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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, and Zito, Karen
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LONG-term synaptic depression , *METHYL aspartate receptors , *PROTEIN precursors , *NEUROPLASTICITY , *LONG-term memory - 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. • AETA hampers NMDA receptor ionotropic activity by competing with its co-agonists • AETA modifies NMDA receptor conformation and enhances ion-flux-independent signaling • AETA level is raised by increased neuronal activity • Deletion of AETA modifies NMDA receptor signaling and associated synapse plasticity Dunot et al. identify AETA, a bioactive cleavage product of amyloid-β precursor protein, as a novel endogenous NMDA receptor regulator. AETA competes with receptor co-agonists, thereby modulating ionotropic and non-ionotropic receptor activities. Chronic AETA loss impairs synaptic plasticity and memory. These findings highlight a new mechanism regulating brain information processing. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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