Home > Publications Database > APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors. > print

001     271713
005     20250127091733.0
024 7 _ |a 10.1016/j.neuron.2024.05.027
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024 7 _ |a 1097-4199
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037 _ _ |a DZNE-2024-01065
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082 _ _ |a 610
100 1 _ |a Dunot, Jade
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245 _ _ |a APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
260 _ _ |a New York, NY
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520 _ _ |a 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.
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650 _ 7 |a APP
|2 Other
650 _ 7 |a NMDA receptors
|2 Other
650 _ 7 |a amyloid-β precursor protein
|2 Other
650 _ 7 |a eta-secretase
|2 Other
650 _ 7 |a hippocampus
|2 Other
650 _ 7 |a long-term depression
|2 Other
650 _ 7 |a memory
|2 Other
650 _ 7 |a non-ionotropic signaling
|2 Other
650 _ 7 |a spine shrinkage
|2 Other
650 _ 7 |a synapse
|2 Other
650 _ 7 |a Receptors, N-Methyl-D-Aspartate
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Protein Precursor
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Receptors, N-Methyl-D-Aspartate: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: metabolism
|2 MeSH
650 _ 2 |a Signal Transduction: physiology
|2 MeSH
650 _ 2 |a Long-Term Synaptic Depression: physiology
|2 MeSH
650 _ 2 |a Long-Term Synaptic Depression: drug effects
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Fear: physiology
|2 MeSH
650 _ 2 |a Hippocampus: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Dendritic Spines: metabolism
|2 MeSH
650 _ 2 |a Memory: physiology
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
700 1 _ |a Moreno, Sebastien
|b 1
700 1 _ |a Gandin, Carine
|b 2
700 1 _ |a Pousinha, Paula A
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700 1 _ |a Amici, Mascia
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700 1 _ |a Dupuis, Julien
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700 1 _ |a Anisimova, Margarita
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700 1 _ |a Winschel, Alex
|b 7
700 1 _ |a Uriot, Magalie
|b 8
700 1 _ |a Petshow, Samuel J
|b 9
700 1 _ |a Mensch, Maria
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700 1 _ |a Bethus, Ingrid
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700 1 _ |a Giudici, Camilla
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700 1 _ |a Hampel, Heike
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700 1 _ |a Wefers, Benedikt
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700 1 _ |a Wurst, Wolfgang
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700 1 _ |a Naumann, Ronald
|b 16
700 1 _ |a Ashby, Michael C
|b 17
700 1 _ |a Laube, Bodo
|b 18
700 1 _ |a Zito, Karen
|b 19
700 1 _ |a Mellor, Jack R
|b 20
700 1 _ |a Groc, Laurent
|b 21
700 1 _ |a Willem, Michael
|b 22
700 1 _ |a Marie, Hélène
|b 23
773 _ _ |a 10.1016/j.neuron.2024.05.027
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