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000271713 0247_ $$2doi$$a10.1016/j.neuron.2024.05.027
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000271713 1001_ $$aDunot, Jade$$b0
000271713 245__ $$aAPP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
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000271713 520__ $$aNMDA 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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000271713 650_7 $$2Other$$aAPP
000271713 650_7 $$2Other$$aNMDA receptors
000271713 650_7 $$2Other$$aamyloid-β precursor protein
000271713 650_7 $$2Other$$aeta-secretase
000271713 650_7 $$2Other$$ahippocampus
000271713 650_7 $$2Other$$along-term depression
000271713 650_7 $$2Other$$amemory
000271713 650_7 $$2Other$$anon-ionotropic signaling
000271713 650_7 $$2Other$$aspine shrinkage
000271713 650_7 $$2Other$$asynapse
000271713 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000271713 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000271713 650_2 $$2MeSH$$aHumans
000271713 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000271713 650_2 $$2MeSH$$aAnimals
000271713 650_2 $$2MeSH$$aMice
000271713 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000271713 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000271713 650_2 $$2MeSH$$aSignal Transduction: physiology
000271713 650_2 $$2MeSH$$aLong-Term Synaptic Depression: physiology
000271713 650_2 $$2MeSH$$aLong-Term Synaptic Depression: drug effects
000271713 650_2 $$2MeSH$$aMice, Inbred C57BL
000271713 650_2 $$2MeSH$$aMice, Knockout
000271713 650_2 $$2MeSH$$aFear: physiology
000271713 650_2 $$2MeSH$$aHippocampus: metabolism
000271713 650_2 $$2MeSH$$aNeurons: metabolism
000271713 650_2 $$2MeSH$$aDendritic Spines: metabolism
000271713 650_2 $$2MeSH$$aMemory: physiology
000271713 650_2 $$2MeSH$$aRats
000271713 7001_ $$aMoreno, Sebastien$$b1
000271713 7001_ $$aGandin, Carine$$b2
000271713 7001_ $$aPousinha, Paula A$$b3
000271713 7001_ $$aAmici, Mascia$$b4
000271713 7001_ $$aDupuis, Julien$$b5
000271713 7001_ $$aAnisimova, Margarita$$b6
000271713 7001_ $$aWinschel, Alex$$b7
000271713 7001_ $$aUriot, Magalie$$b8
000271713 7001_ $$aPetshow, Samuel J$$b9
000271713 7001_ $$aMensch, Maria$$b10
000271713 7001_ $$aBethus, Ingrid$$b11
000271713 7001_ $$0P:(DE-2719)2812582$$aGiudici, Camilla$$b12$$udzne
000271713 7001_ $$aHampel, Heike$$b13
000271713 7001_ $$0P:(DE-2719)2810988$$aWefers, Benedikt$$b14$$udzne
000271713 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b15$$udzne
000271713 7001_ $$aNaumann, Ronald$$b16
000271713 7001_ $$aAshby, Michael C$$b17
000271713 7001_ $$aLaube, Bodo$$b18
000271713 7001_ $$aZito, Karen$$b19
000271713 7001_ $$aMellor, Jack R$$b20
000271713 7001_ $$aGroc, Laurent$$b21
000271713 7001_ $$aWillem, Michael$$b22
000271713 7001_ $$aMarie, Hélène$$b23
000271713 773__ $$0PERI:(DE-600)2001944-0$$a10.1016/j.neuron.2024.05.027$$gVol. 112, no. 16, p. 2708 - 2720.e9$$n16$$p2708 - 2720.e9$$tNeuron$$v112$$x0896-6273$$y2024
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