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

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 mechan...

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Autores principales: Jézéquel, Julie, Johansson, Emily M., Dupuis, Julien P., Rogemond, Véronique, Gréa, Hélène, 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, Jérôme, Leboyer, Marion, Groc, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702610/
https://www.ncbi.nlm.nih.gov/pubmed/29176681
http://dx.doi.org/10.1038/s41467-017-01700-3
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author Jézéquel, Julie
Johansson, Emily M.
Dupuis, Julien P.
Rogemond, Véronique
Gréa, Hélène
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, Jérôme
Leboyer, Marion
Groc, Laurent
author_facet Jézéquel, Julie
Johansson, Emily M.
Dupuis, Julien P.
Rogemond, Véronique
Gréa, Hélène
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, Jérôme
Leboyer, Marion
Groc, Laurent
author_sort Jézéquel, Julie
collection PubMed
description 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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spelling pubmed-57026102017-11-29 Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients Jézéquel, Julie Johansson, Emily M. Dupuis, Julien P. Rogemond, Véronique Gréa, Hélène 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, Jérôme Leboyer, Marion Groc, Laurent Nat Commun Article 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. Nature Publishing Group UK 2017-11-27 /pmc/articles/PMC5702610/ /pubmed/29176681 http://dx.doi.org/10.1038/s41467-017-01700-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jézéquel, Julie
Johansson, Emily M.
Dupuis, Julien P.
Rogemond, Véronique
Gréa, Hélène
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, Jérôme
Leboyer, Marion
Groc, Laurent
Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title_full Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title_fullStr Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title_full_unstemmed Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title_short Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
title_sort dynamic disorganization of synaptic nmda receptors triggered by autoantibodies from psychotic patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702610/
https://www.ncbi.nlm.nih.gov/pubmed/29176681
http://dx.doi.org/10.1038/s41467-017-01700-3
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