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Published on: August 1, 2011
A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal
Yasuhiro Ishihara1,2, Tatsuya Honda3, Nami Ishihara3
1Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-7-1, Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8521, Japan. ishiyasu@hiroshima-u.ac.jp.
Insights
Prenatal exposure to valproic acid (VPA) activates microglia, leading to neurodevelopmental and behavioral issues in offspring. Targeting microglial CCL3 with CCR5 antagonists may offer therapeutic potential for VPA-induced abnormalities.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Valproic acid (VPA) is an antiepileptic drug linked to neurodevelopmental risks like low IQ, ADHD, and ASD in children exposed prenatally.
- Prenatal VPA exposure impacts neurogenesis, neuronal migration, and differentiation.
- VPA treatment activates microglia, but their specific role in VPA-induced neurodevelopmental deficits remains unclear.
Purpose of the Study:
- To investigate the role of VPA-activated microglia in neurodevelopmental and behavioral abnormalities.
- To explore the potential therapeutic effects of microglial inhibitors and CCR5 antagonists on VPA-induced effects.
Main Methods:
- Pregnant mice received VPA on E11.5. Dams were treated with minocycline (microglial inhibitor) or maraviroc (CCR5 antagonist) from P1 to P21.
- Microglial activity, neural circuit function, and gene expression were analyzed on P10.
- Behavioral tests (open field, Y-maze, social affiliation, marble burying) were conducted from 6 weeks of age.
Main Results:
- Prenatal VPA exposure induced microglial activation and hippocampal CA1 neural circuit dysfunction, leading to working memory deficits, impaired social interaction, and repetitive behaviors.
- Minocycline treatment ameliorated these VPA-induced effects, implicating microglia in neural dysfunction and behavioral disorders.
- Upregulation of chemokine CCL3 in microglia was observed, and the CCR5 antagonist maraviroc significantly mitigated VPA-induced neural and behavioral deficits.
Conclusions:
- Microglial CCL3 plays a developmental role in VPA-induced behavioral abnormalities.
- CCR5-targeting agents like maraviroc show promise for alleviating VPA-induced behavioral disorders when administered early in development.
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.
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