Abstract
Rationale
Adequate immunotherapies for anti-NMDAR encephalitis during pregnancy produce a relatively good clinical outcome for pregnant mothers and their infants, but there are no reports about the future growth of their babies. The damage of anti-NMDAR antibodies to early neuronal development is still unknown.
Objectives
Serum or cerebrospinal fluid from one patient with anti-NMDAR encephalitis (the index patient) and one patient with schizophrenia (the control patient) was administered to primary cultures of dissociated rat cortical neurons, and dendritic outgrowth, centrosome elimination, and branching of dendrites were investigated. For rescue experiments, serum of the index patient was replaced with normal culture media after 3 days’ administration of the index patient.
Results
Serum and cerebrospinal fluid of the index patient statistically significantly impaired dendritic outgrowth of cultured rat cortical primary neurons. Serum of the index patient also statistically significantly delayed centrosome elimination. Impaired dendritic outgrowth and delayed centrosome elimination were not perfectly rescued by changing to normal culture media. Serum of the index patient also statistically significantly reduced the branching of dendrites.
Conclusions
This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.
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Acknowledgements
The authors would like to thank the Zikei Institute of Psychiatry (Okayama, Japan) for support.
Funding
This research was founded in part by the JSPS KAKENHI Grant Number 16K10188 and 19K08019 (Manabu Takaki), Kobayashi Magobe Memorial Medical Foundation (Manabu Takaki), the Okayama Medical Foundation (Manabu Takaki), the Japan Epilepsy Research Foundation (Manabu Takaki), and the Senshin Medical Research Foundation (Manabu Takaki). Article processing charges are covered by JSPS KAKENHI Grant Number 19K08019.
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S. Okamoto, M. Takaki, Sakamoto, Y. Okahisa, K. Tsutsui, T. Kanbayashi, K. Tanaka, and N. Yamada participated in the design of the study, supervised the project, and contributed intellectually to the interpretation of the data. S. Okamoto, M. Takaki, S. K. Hinotsu, H. Kawai, and S. Takao interpreted the experiment and the statistical analyses. All authors contributed to and have approved the final manuscript.
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Fig. S1.
Impairment of dendritic outgrowth by administration of serum or CSF of the patient with anti-NMDAR encephalitis (day 3 in vitro). Serum (1:100) or CSF (1:20) of patients with or without anti-NMDAR antibodies was administered to the medium from 0 day in vitro (D.I.V.) to 3 D.I.V. Cultured neurons were fixed by methanol and incubated with 1:300 MAP2 (primary antibody). Statistical analysis was performed by one-way ANOVA following a Kruskal-Wallis test, *P<0.05. (PPTX 3218 kb)
Fig. S2.
Gradual elimination of centrosome marker, γ-tubulin. On D.I.V. 0, 3, 7, 14, cortical neurons were fixed by methanol and were incubated with 1:50 γ-tubulin (primary antibodies). Following dendritic maturation, gradual elimination of the centrosome marker γ-tubulin was shown, and γ-tubulin was almost eliminated by D.I.V. 7. (PPTX 2314 kb)
Fig. S3.
Impairment of centrosome elimination by serum of the patient with anti-NMDAR encephalitis (day 3 in vitro). Serum (1:100) of patients with or without anti NMDAR antibodies was administered to the medium from day 0 in vitro (D.I.V.) to 3 D.I.V. Cortical neurons were fixed by methanol and incubated with 1:50 γ-tubulin (primary antibodies). White arrows indicate centrosomes. Statistical analysis was performed by one-way ANOVA following Kruskal-Wallis test, *P<0.05. (PPTX 2331 kb)
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Okamoto, S., Takaki, M., Hinotsu, K. et al. Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis. Psychopharmacology 239, 525–531 (2022). https://doi.org/10.1007/s00213-021-06036-x
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DOI: https://doi.org/10.1007/s00213-021-06036-x