Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
Nat Commun. 2017-11-27; 8(1):
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Jézéquel J(1)(2), Johansson EM(1)(2), Dupuis JP(1)(2), Rogemond V(3)(4)(5), Gréa H(1)(2), Kellermayer B(1)(2), Hamdani N(6)(7)(8), Le Guen E(6)(7)(8), Rabu C(6)(7)(8), Lepleux M(1)(2), Spatola M(9), Mathias E(3)(4)(5), Bouchet D(1)(2), Ramsey AJ(10), Yolken RH(11), Tamouza R(12)(13), Dalmau J(9)(14), Honnorat J(3)(4)(5), Leboyer M(6)(7)(8), Groc L(15)(16).
(1)Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, France.
(2)CNRS, IINS UMR 5297, 33077, Bordeaux, France.
(3)Institut NeuroMyoGene INSERM U1217/CNRS, UMR 5310, Lyon, 69007, France.
(4)Hospices Civils de Lyon, Hôpital Neurologique, 69677, Bron, France.
(5)Université de Lyon-Université Claude Bernard Lyon 1, 69008, Lyon, France.
(6)University Paris Est Créteil, Psychiatry department, Hopitaux Universitaires Henri Mondor, AP-HP, DHU PePSY, 94010, Créteil, France.
(7)Translational Psychiatry Laboratory, INSERM U955, 94010, Créteil, France.
(8)FondaMental Foundation, 94010, Créteil, France.
(9)Biomedical Research Institute August Pi i Sunyer (IDIBAPS), University of Barcelona, Catalan Institution for Research and Advanced Studies (ICREA), 08036, Barcelona, Spain.
(10)Department of Physiology, Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada, M5S 1A8.
(11)The Johns Hopkins University School of Medicine, Stanley Division of Developmental Neurovirology, Baltimore, MD, 21287, USA.
(12)INSERM, U1160, Hôpital Saint Louis, Paris, F75010, France.
(13)Laboratoire Jean Dausset, LabEx Transplantex, Hôpital Saint Louis, Paris, F75010, France.
(14)Department of Neurology, University of Pennsylvania, Pennsylvania, PA, 19104, USA.
(15)Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, France. .
(16)CNRS, IINS UMR 5297, 33077, Bordeaux, France. .
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.