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; Laurent Groc

doi:10.1038/s41467-017-01700-3

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, Laurent Groc

School of Medicine

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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.

Original language	English (US)
Article number	1791
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01700-3
State	Published - Dec 1 2017

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-017-01700-3

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Jézéquel, J., Johansson, E. M., Dupuis, J. P., Rogemond, V., Gréa, H., Kellermayer, B., Hamdani, N., Le Guen, E., Rabu, C., Lepleux, M., Spatola, M., Mathias, E., Bouchet, D., Ramsey, A. J., Yolken, R. H., Tamouza, R., Dalmau, J., Honnorat, J., Leboyer, M., & Groc, L. (2017). Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nature communications, 8(1), Article 1791. https://doi.org/10.1038/s41467-017-01700-3

Jézéquel, J, Johansson, EM, Dupuis, JP, Rogemond, V, Gréa, H, Kellermayer, B, Hamdani, N, Le Guen, E, Rabu, C, Lepleux, M, Spatola, M, Mathias, E, Bouchet, D, Ramsey, AJ, Yolken, RH, Tamouza, R, Dalmau, J, Honnorat, J, Leboyer, M & Groc, L 2017, 'Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients', Nature communications, vol. 8, no. 1, 1791. https://doi.org/10.1038/s41467-017-01700-3

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title = "Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients",

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.",

author = "Julie J{\'e}z{\'e}quel and Johansson, {Emily M.} and Dupuis, {Julien P.} and V{\'e}ronique Rogemond and H{\'e}l{\`e}ne Gr{\'e}a and Blanka Kellermayer and Nora Hamdani and {Le Guen}, Emmanuel and Corentin Rabu and Marilyn Lepleux and Marianna Spatola and Elodie Mathias and Delphine Bouchet and Ramsey, {Amy J.} and Yolken, {Robert H.} and Ryad Tamouza and Josep Dalmau and J{\'e}r{\^o}me Honnorat and Marion Leboyer and Laurent Groc",

note = "Funding Information: This work was supported by the Centre National de la Recherche Scientifique, Agence Nationale de la Recherche (ANR-12-SAMA-0014), Fondation pour la Recherche M{\'e}d-icale, Conseil R{\'e}gional d{\textquoteright}Aquitaine, Labex Bordeaux BRAIN, IDEX Bordeaux, fondation FondaMental, Labex Bio-PSY, and Minist{\`e}re de l{\textquoteright}Enseignement sup{\'e}rieur et de la Recherche. We thank the Bordeaux Imaging Center (service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging) for confocal and STORM imaging, and J.B. Sibarita for STORM analysis. We thank Charlotte Bertot and Pauline Durand for technical assistance on cell cultures, molecular biology, and immunohistochemistry, Daniel Jercog for calcium imaging analysis, and lab members for constructive discussions. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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doi = "10.1038/s41467-017-01700-3",

language = "English (US)",

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T1 - Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients

AU - Jézéquel, Julie

AU - Johansson, Emily M.

AU - Dupuis, Julien P.

AU - Rogemond, Véronique

AU - Gréa, Hélène

AU - Kellermayer, Blanka

AU - Hamdani, Nora

AU - Le Guen, Emmanuel

AU - Rabu, Corentin

AU - Lepleux, Marilyn

AU - Spatola, Marianna

AU - Mathias, Elodie

AU - Bouchet, Delphine

AU - Ramsey, Amy J.

AU - Yolken, Robert H.

AU - Tamouza, Ryad

AU - Dalmau, Josep

AU - Honnorat, Jérôme

AU - Leboyer, Marion

AU - Groc, Laurent

N1 - Funding Information: This work was supported by the Centre National de la Recherche Scientifique, Agence Nationale de la Recherche (ANR-12-SAMA-0014), Fondation pour la Recherche Méd-icale, Conseil Régional d’Aquitaine, Labex Bordeaux BRAIN, IDEX Bordeaux, fondation FondaMental, Labex Bio-PSY, and Ministère de l’Enseignement supérieur et de la Recherche. We thank the Bordeaux Imaging Center (service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging) for confocal and STORM imaging, and J.B. Sibarita for STORM analysis. We thank Charlotte Bertot and Pauline Durand for technical assistance on cell cultures, molecular biology, and immunohistochemistry, Daniel Jercog for calcium imaging analysis, and lab members for constructive discussions. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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

Abstract

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