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@ARTICLE{Jamet:271072,
      author       = {Jamet, Zoe and Mergaux, Camille and Meras, Morgane and
                      Bouchet, Delphine and Villega, Frédéric and Kreye, Jakob
                      and Prüss, Harald and Groc, Laurent},
      title        = {{NMDA} receptor autoantibodies primarily impair the
                      extrasynaptic compartment.},
      journal      = {Brain},
      volume       = {147},
      number       = {8},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2024-00944},
      pages        = {2745 - 2760},
      year         = {2024},
      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.},
      keywords     = {Receptors, N-Methyl-D-Aspartate: immunology / Receptors,
                      N-Methyl-D-Aspartate: metabolism / Autoantibodies:
                      immunology / Autoantibodies: pharmacology / Animals /
                      Hippocampus: metabolism / Neurons: metabolism / Rats /
                      Synapses: metabolism / Humans / Cells, Cultured / Receptor,
                      EphB2: metabolism / Mice / Anti-N-Methyl-D-Aspartate
                      Receptor Encephalitis: immunology / autoantibody (Other) /
                      encephalitis (Other) / extrasynaptic NMDA receptor (Other) /
                      interactome (Other) / membrane proteins (Other) / Receptors,
                      N-Methyl-D-Aspartate (NLM Chemicals) / Autoantibodies (NLM
                      Chemicals) / Receptor, EphB2 (NLM Chemicals)},
      cin          = {AG Prüß},
      ddc          = {610},
      cid          = {I:(DE-2719)1810003},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38758090},
      pmc          = {pmc:PMC11292910},
      doi          = {10.1093/brain/awae163},
      url          = {https://pub.dzne.de/record/271072},
}