TY  - JOUR
AU  - Jamet, Zoe
AU  - Mergaux, Camille
AU  - Meras, Morgane
AU  - Bouchet, Delphine
AU  - Villega, Frédéric
AU  - Kreye, Jakob
AU  - Prüss, Harald
AU  - Groc, Laurent
TI  - NMDA receptor autoantibodies primarily impair the extrasynaptic compartment.
JO  - Brain
VL  - 147
IS  - 8
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2024-00944
SP  - 2745 - 2760
PY  - 2024
AB  - 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.
KW  - Receptors, N-Methyl-D-Aspartate: immunology
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Autoantibodies: immunology
KW  - Autoantibodies: pharmacology
KW  - Animals
KW  - Hippocampus: metabolism
KW  - Neurons: metabolism
KW  - Rats
KW  - Synapses: metabolism
KW  - Humans
KW  - Cells, Cultured
KW  - Receptor, EphB2: metabolism
KW  - Mice
KW  - Anti-N-Methyl-D-Aspartate Receptor Encephalitis: immunology
KW  - autoantibody (Other)
KW  - encephalitis (Other)
KW  - extrasynaptic NMDA receptor (Other)
KW  - interactome (Other)
KW  - membrane proteins (Other)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
KW  - Autoantibodies (NLM Chemicals)
KW  - Receptor, EphB2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38758090
C2  - pmc:PMC11292910
DO  - DOI:10.1093/brain/awae163
UR  - https://pub.dzne.de/record/271072
ER  -