Journal Article

DZNE-2024-00944

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NMDA receptor autoantibodies primarily impair the extrasynaptic compartment.

Jamet, Z. ; Mergaux, C. ; Meras, M. ; Bouchet, D. ; Villega, F. ; Kreye, J.DZNE* ; Prüss, H.DZNE* ; Groc, L.

2024
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awae163

Abstract: Autoantibodies 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.

Keyword(s): Receptors, N-Methyl-D-Aspartate: immunology (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Autoantibodies: immunology (MeSH) ; Autoantibodies: pharmacology (MeSH) ; Animals (MeSH) ; Hippocampus: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Rats (MeSH) ; Synapses: metabolism (MeSH) ; Humans (MeSH) ; Cells, Cultured (MeSH) ; Receptor, EphB2: metabolism (MeSH) ; Mice (MeSH) ; Anti-N-Methyl-D-Aspartate Receptor Encephalitis: immunology (MeSH) ; autoantibody ; encephalitis ; extrasynaptic NMDA receptor ; interactome ; membrane proteins ; Receptors, N-Methyl-D-Aspartate ; Autoantibodies ; Receptor, EphB2

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Contributing Institute(s):

1. Autoimmune Encephalopathies (AG Prüß)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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