The Impact of Valproic Acid on Microbiota in a Mouse Model of Autism Spectrum Disorder.

Abstract

Background: Autism spectrum disorder (ASD) is a complex neuropsychiatric condition with a multifactorial etiology, involving both genetic predisposition and environmental factors. Valproic acid (VPA), a commonly used antiepileptic drug, has been shown to induce ASD-like behaviors in rodent models, making it a valuable tool for studying the pathophysiology of ASD. This study aims to explore the effects of VPA on behavior and the microbiota in a mouse model of ASD.

Methods: C57BL/6 mice were used in this study, with pregnant females receiving a single intraperitoneal injection of VPA (450 mg/kg) or a saline solution on gestational day E12.5. Behavioral assessments, including the Three-Chamber Social Test, Elevated Plus Maze, Marble Burying Test, Open Field Test, and Light-Dark Box Test, were conducted on 8-week-old mice. Oral and fecal samples were collected for microbiota analysis, and gene expression profiling was performed on brain samples.

Results: VPA-treated mice exhibited significant deficits in social interaction, anxiety-like behaviors, and repetitive actions. Microbiota analysis revealed significant shifts in the composition of both oral and fecal microbial communities in VPA-treated mice, with reductions in alpha diversity and changes in the relative abundance of specific taxa. Gene set variation analysis of mice harboring VPA-induced microbiota identified notable discrepancies in metabolic pathways, suggesting that the dysbiosis may modulate the expression of genes involved in critical metabolic processes.

Conclusion: The present study provides evidence that VPA exposure during early development can induce ASD-like behaviors in mice, along with significant changes in the composition of the microbiota. These findings underscore the complex interplay between environmental factors, such as VPA, and the microbiota in the pathophysiology of ASD. The study lays the groundwork for future research aimed at developing targeted interventions to mitigate the symptoms of ASD and other neuropsychiatric disorders, potentially through modulating the microbiota-gut-brain axis.