Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ishihara, Yasuhiro, Honda, Tatsuya, Ishihara, Nami, Namba, Kaede, Taketoshi, Makiko, Tominaga, Yoko, Tsuji, Mayumi, Vogel, Christoph F. A., Yamazaki, Takeshi, Itoh, Kouichi, Tominaga, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335995/
https://www.ncbi.nlm.nih.gov/pubmed/35906621
http://dx.doi.org/10.1186/s12974-022-02559-y
_version_ 1784759452693430272
author Ishihara, Yasuhiro
Honda, Tatsuya
Ishihara, Nami
Namba, Kaede
Taketoshi, Makiko
Tominaga, Yoko
Tsuji, Mayumi
Vogel, Christoph F. A.
Yamazaki, Takeshi
Itoh, Kouichi
Tominaga, Takashi
author_facet Ishihara, Yasuhiro
Honda, Tatsuya
Ishihara, Nami
Namba, Kaede
Taketoshi, Makiko
Tominaga, Yoko
Tsuji, Mayumi
Vogel, Christoph F. A.
Yamazaki, Takeshi
Itoh, Kouichi
Tominaga, Takashi
author_sort Ishihara, Yasuhiro
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02559-y.
format Online
Article
Text
id pubmed-9335995
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-93359952022-07-30 A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure Ishihara, Yasuhiro Honda, Tatsuya Ishihara, Nami Namba, Kaede Taketoshi, Makiko Tominaga, Yoko Tsuji, Mayumi Vogel, Christoph F. A. Yamazaki, Takeshi Itoh, Kouichi Tominaga, Takashi J Neuroinflammation Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02559-y. BioMed Central 2022-07-29 /pmc/articles/PMC9335995/ /pubmed/35906621 http://dx.doi.org/10.1186/s12974-022-02559-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ishihara, Yasuhiro
Honda, Tatsuya
Ishihara, Nami
Namba, Kaede
Taketoshi, Makiko
Tominaga, Yoko
Tsuji, Mayumi
Vogel, Christoph F. A.
Yamazaki, Takeshi
Itoh, Kouichi
Tominaga, Takashi
A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title_full A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title_fullStr A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title_full_unstemmed A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title_short A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
title_sort ccr5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335995/
https://www.ncbi.nlm.nih.gov/pubmed/35906621
http://dx.doi.org/10.1186/s12974-022-02559-y
work_keys_str_mv AT ishiharayasuhiro accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT hondatatsuya accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT ishiharanami accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT nambakaede accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT taketoshimakiko accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tominagayoko accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tsujimayumi accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT vogelchristophfa accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT yamazakitakeshi accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT itohkouichi accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tominagatakashi accr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT ishiharayasuhiro ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT hondatatsuya ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT ishiharanami ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT nambakaede ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT taketoshimakiko ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tominagayoko ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tsujimayumi ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT vogelchristophfa ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT yamazakitakeshi ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT itohkouichi ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure
AT tominagatakashi ccr5antagonistmaravirocalleviatesneuralcircuitdysfunctionandbehavioraldisordersinducedbyprenatalvalproateexposure