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  Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.

Pan, H., Steixner-Kumar, A. A., Seelbach, A., Deutsch, N., Ronnenberg, A., Tapken, D., et al. (2021). Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury. Molecular Psychiatry, 26(6), 2471-2482. doi:10.1038/s41380-020-0672-1.

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 Creators:
Pan, H.1, Author              
Steixner-Kumar, A. A.1, Author              
Seelbach, A.1, Author              
Deutsch, N., Author
Ronnenberg, A.1, Author              
Tapken, D., Author
von Ahsen, N., Author
Mitjans, M.1, Author              
Worthmann, H., Author
Trippe, R., Author
Klein-Schmidt, C., Author
Schopf, N.1, Author              
Rentzsch, K., Author
Begemann, M.1, Author              
Wienands, J., Author
Stöcker, W., Author
Weissenborn, K., Author
Hollmann, M., Author
Nave, K.-A.2, Author              
Lühder, F., Author
Ehrenreich, H.1, Author               more..
Affiliations:
1Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173651              
2Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173664              

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 Abstract: Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood–brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

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Language(s): eng - English
 Dates: 2020-02-242021-06
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41380-020-0672-1
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Title: Molecular Psychiatry
Source Genre: Journal
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Pages: - Volume / Issue: 26 (6) Sequence Number: - Start / End Page: 2471 - 2482 Identifier: -