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

Julie Jézéquel, Emily M. Johansson, Julien P. Dupuis, Véronique Rogemond, Hélène Gréa, Blanka Kellermayer, Nora Hamdani, Emmanuel Le Guen, Corentin Rabu, Marilyn Lepleux, Marianna Spatola, Elodie Mathias, Delphine Bouchet, Amy J. Ramsey, Robert H. Yolken, Ryad Tamouza, Josep Dalmau, Jérôme Honnorat, Marion Leboyer and Laurent Groc ()
Additional contact information
Julie Jézéquel: Interdisciplinary Institute for Neuroscience
Emily M. Johansson: Interdisciplinary Institute for Neuroscience
Julien P. Dupuis: Interdisciplinary Institute for Neuroscience
Véronique Rogemond: Institut NeuroMyoGene INSERM U1217/CNRS
Hélène Gréa: Interdisciplinary Institute for Neuroscience
Blanka Kellermayer: Interdisciplinary Institute for Neuroscience
Nora Hamdani: DHU PePSY
Emmanuel Le Guen: DHU PePSY
Corentin Rabu: DHU PePSY
Marilyn Lepleux: Interdisciplinary Institute for Neuroscience
Marianna Spatola: University of Barcelona, Catalan Institution for Research and Advanced Studies (ICREA)
Elodie Mathias: Institut NeuroMyoGene INSERM U1217/CNRS
Delphine Bouchet: Interdisciplinary Institute for Neuroscience
Amy J. Ramsey: University of Toronto
Robert H. Yolken: Stanley Division of Developmental Neurovirology
Ryad Tamouza: Hôpital Saint Louis
Josep Dalmau: University of Barcelona, Catalan Institution for Research and Advanced Studies (ICREA)
Jérôme Honnorat: Institut NeuroMyoGene INSERM U1217/CNRS
Marion Leboyer: DHU PePSY
Laurent Groc: Interdisciplinary Institute for Neuroscience

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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 autoantibodies 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.

Date: 2017
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DOI: 10.1038/s41467-017-01700-3

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