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

Authors
Jade Dunot, Sebastien Moreno, Carine Gandin, Paula A. Pousinha, Mascia Amici, Julien Dupuis, Margarita Anisimova, Alex Winschel, Magalie Uriot, Samuel J. Petshow, Maria Mensch, Ingrid Bethus, Camilla Giudici, Heike Hampel, Benedikt Wefers, Wolfgang Wurst, Ronald Naumann, Michael C. Ashby, Bodo Laube, Karen Zito, Jack R. Mellor, Laurent Groc, Michael Willem, H©l¨ne Marie


Lab

Journal
Neuron

Abstract

Summary

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 (A·), an amyloid-Beta 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 invivo 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.

Keywords/Topics
NMDA receptors non - ionotropic signaling amyloid; precursor protein APP eta ;secretase; synapse; hippocampus ;spine ;shrinkage

Source :

https://www.cell.com/neuron/fulltext/S0896-6273(24)00404-5

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