TY  - JOUR
AU  - Dunot, Jade
AU  - Moreno, Sebastien
AU  - Gandin, Carine
AU  - Pousinha, Paula A
AU  - Amici, Mascia
AU  - Dupuis, Julien
AU  - Anisimova, Margarita
AU  - Winschel, Alex
AU  - Uriot, Magalie
AU  - Petshow, Samuel J
AU  - Mensch, Maria
AU  - Bethus, Ingrid
AU  - Giudici, Camilla
AU  - Hampel, Heike
AU  - Wefers, Benedikt
AU  - Wurst, Wolfgang
AU  - Naumann, Ronald
AU  - Ashby, Michael C
AU  - Laube, Bodo
AU  - Zito, Karen
AU  - Mellor, Jack R
AU  - Groc, Laurent
AU  - Willem, Michael
AU  - Marie, Hélène
TI  - APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
JO  - Neuron
VL  - 112
IS  - 16
SN  - 0896-6273
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2024-01065
SP  - 2708 - 2720.e9
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Animals
KW  - Mice
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Signal Transduction: physiology
KW  - Long-Term Synaptic Depression: physiology
KW  - Long-Term Synaptic Depression: drug effects
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Fear: physiology
KW  - Hippocampus: metabolism
KW  - Neurons: metabolism
KW  - Dendritic Spines: metabolism
KW  - Memory: physiology
KW  - Rats
KW  - APP (Other)
KW  - NMDA receptors (Other)
KW  - amyloid-β precursor protein (Other)
KW  - eta-secretase (Other)
KW  - hippocampus (Other)
KW  - long-term depression (Other)
KW  - memory (Other)
KW  - non-ionotropic signaling (Other)
KW  - spine shrinkage (Other)
KW  - synapse (Other)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38878768
C2  - pmc:PMC11343662
DO  - DOI:10.1016/j.neuron.2024.05.027
UR  - https://pub.dzne.de/record/271713
ER  -