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000271072 041__ $$aEnglish
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000271072 1001_ $$aJamet, Zoe$$b0
000271072 245__ $$aNMDA receptor autoantibodies primarily impair the extrasynaptic compartment.
000271072 260__ $$aOxford$$bOxford Univ. Press$$c2024
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000271072 520__ $$aAutoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological and psychiatric symptoms in patients. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to an unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented. Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatiotemporal action of NMDAR-Ab on live hippocampal neurons. We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic (and not synaptic) NMDARs. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, declustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located in the extrasynaptic compartment. Consistent with this alteration of multiple proteins, effects of NMDAR-Ab were not mediated through the sole interaction between the NMDAR and EphB2 receptor. In the long term, NMDAR-Ab reduce the NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking-independent manner. Remarkably, exposing only extrasynaptic NMDARs to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors. Collectively, we demonstrate that NMDAR-Ab initially impair extrasynaptic proteins, then the synaptic ones. These data thus shed new and unsuspected light on the mode of action of NMDAR-Ab and, probably, our understanding of (extra)synaptopathies.
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000271072 650_7 $$2Other$$aautoantibody
000271072 650_7 $$2Other$$aencephalitis
000271072 650_7 $$2Other$$aextrasynaptic NMDA receptor
000271072 650_7 $$2Other$$ainteractome
000271072 650_7 $$2Other$$amembrane proteins
000271072 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000271072 650_7 $$2NLM Chemicals$$aAutoantibodies
000271072 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, EphB2
000271072 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: immunology
000271072 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000271072 650_2 $$2MeSH$$aAutoantibodies: immunology
000271072 650_2 $$2MeSH$$aAutoantibodies: pharmacology
000271072 650_2 $$2MeSH$$aAnimals
000271072 650_2 $$2MeSH$$aHippocampus: metabolism
000271072 650_2 $$2MeSH$$aNeurons: metabolism
000271072 650_2 $$2MeSH$$aRats
000271072 650_2 $$2MeSH$$aSynapses: metabolism
000271072 650_2 $$2MeSH$$aHumans
000271072 650_2 $$2MeSH$$aCells, Cultured
000271072 650_2 $$2MeSH$$aReceptor, EphB2: metabolism
000271072 650_2 $$2MeSH$$aMice
000271072 650_2 $$2MeSH$$aAnti-N-Methyl-D-Aspartate Receptor Encephalitis: immunology
000271072 7001_ $$aMergaux, Camille$$b1
000271072 7001_ $$aMeras, Morgane$$b2
000271072 7001_ $$aBouchet, Delphine$$b3
000271072 7001_ $$aVillega, Frédéric$$b4
000271072 7001_ $$0P:(DE-2719)2811468$$aKreye, Jakob$$b5$$udzne
000271072 7001_ $$0P:(DE-2719)2810931$$aPrüss, Harald$$b6$$udzne
000271072 7001_ $$00000-0003-1814-8145$$aGroc, Laurent$$b7
000271072 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awae163$$gVol. 147, no. 8, p. 2745 - 2760$$n8$$p2745 - 2760$$tBrain$$v147$$x0006-8950$$y2024
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