Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients

作者：Jezequel Julie; Johansson Emily M; Dupuis Julien P; Rogemond Veronique; Grea Helene; Kellermayer Blanka; Hamdani Nora; Le Guen Emmanuel; Rabu Corentin; Lepleux Marilyn; Spatola Marianna; Mathias Elodie; Bouchet Delphine; Ramsey Amy J; Yolken Robert H; Tamouza Ryad; Dalmau Josep; Honnorat Jerome; Leboyer Marion; Groc Laurent^*

来源：Nature Communications, 2017, 8(1): 1791.

DOI：10.1038/s41467-017-01700-3

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating auto-antibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.

• 出版日期2017-11-27