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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Minocycline | Research

A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure

Authors: Yasuhiro Ishihara, Tatsuya Honda, Nami Ishihara, Kaede Namba, Makiko Taketoshi, Yoko Tominaga, Mayumi Tsuji, Christoph F. A. Vogel, Takeshi Yamazaki, Kouichi Itoh, Takashi Tominaga

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear.

Methods

Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks.

Results

Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C–C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure.

Conclusion

These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.
Appendix
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Metadata
Title
A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
Authors
Yasuhiro Ishihara
Tatsuya Honda
Nami Ishihara
Kaede Namba
Makiko Taketoshi
Yoko Tominaga
Mayumi Tsuji
Christoph F. A. Vogel
Takeshi Yamazaki
Kouichi Itoh
Takashi Tominaga
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02559-y

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