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  NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance

Arinrad, S., Wilke, J. B. H., Seelbach, A., Doeren, J., Hindermann, M., Butt, U. J., et al. (2021). NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance. Molecular Psychiatry, In Press. doi:10.1038/s41380-021-01392-8.

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 Creators:
Arinrad, S.1, Author           
Wilke, J. B. H.1, Author           
Seelbach, A.1, Author           
Doeren, J.1, Author           
Hindermann, M.1, Author           
Butt, U. J.1, Author           
Steixner-Kumar, A. A.1, Author           
Spieth, L.2, Author           
Ronnenberg, A.1, Author           
Pan, H.1, Author           
Berghoff, S. A.2, Author           
Hollmann, M., Author
Lüder, F., Author
Nave, K.-A.2, Author           
Bechter, K., Author
Ehrenreich, H.1, Author           
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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Free keywords: NMDAR1-AB, encephalitis, white matter, genetics
 Abstract: Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.

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Language(s): eng - English
 Dates: 2021-12-06
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41380-021-01392-8
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Project name : This study was supported by the Max Planck Society, the Deutsche Forschungsge- meinschaft (DFG, German Research Foundation) TRR 274/1 2020 - 408885537. K-AN was funded by Adelson Medical Research Foundation and an ERC Advanced Grant.
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Funding program : -
Funding organization : -
Project name : MyeliNano
Grant ID : 671048
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Molecular Psychiatry
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: In Press Start / End Page: - Identifier: ISSN: 1359-4184
ISSN: 1476-5578