Hippocampal Morphological Alterations and Oxidative Stress in Autism Spectrum Disorder Model Induced by Prenatal Exposure to Valproic Acid in Male and Female Mice.

This study used mice to understand how a medication called valproic acid might contribute to autism when taken during pregnancy. Baby mice exposed to this medication before birth showed autism-like behaviors such as being less social, repeating behaviors more, and having memory problems. The researchers found that male and female mice were affected differently in their brain structure, and both had signs of cell damage in the brain area important for learning and memory.

This animal study examined how prenatal exposure to valproic acid (VPA), an antiepileptic medication, affects brain structure and function in mice, serving as a model for autism spectrum disorder. Researchers administered VPA to pregnant mice and later assessed their offspring for autism-like behaviors and brain changes. Results showed VPA exposure induced autism-like behaviors including reduced sociability, increased repetitive behaviors, and working memory problems. Brain analysis revealed sex-specific changes in hippocampal neuron structure and increased oxidative stress.

Male mice showed increased dendritic branching while females showed reduced branching in certain brain regions. Both sexes exhibited higher dendritic spine density and oxidative stress markers, suggesting these mechanisms may contribute to autism development.

Findings support caution regarding VPA use during pregnancy and highlight the importance of discussing autism risk with healthcare providers. The identification of sex-specific brain changes may inform future research into personalized interventions and help explain why autism affects males and females differently.

This is an animal study using mice, so findings may not directly translate to humans. Sample size was not reported, making it difficult to assess study power. The study examined only one time point and dose of VPA exposure, limiting generalizability to different exposure scenarios.

Valproic acid (VPA), a first-line antiepileptic and mood-stabilizing drug, has been linked to congenital malformations, cognitive disabilities, and an elevated risk of autism spectrum disorder (ASD) when used during pregnancy. ASD is a lifelong developmental disorder characterized by impaired social interaction, repetitive behaviors, and cognitive deficits, with a higher prevalence in males. Growing evidence highlights that hippocampal circuits, particularly CA1 and dentate gyrus (DG) subregions, are crucial for cognitive and social functions often impaired in ASD. Notably, VPA exposure at embryonic day 12.5 (E12.5) coincides with critical neurodevelopmental processes in the hippocampus, making it highly susceptible to oxidative damage and structural disruptions.

Using a mouse model of ASD induced by a single prenatal VPA injection (400 mg/kg) at E12.5, this study assessed morphological and oxidative changes in the hippocampus. Male and female offspring were evaluated for core behavioral and cognitive alterations of ASD. After the behavioral tests, their brains were processed for Golgi-Cox staining and antioxidant enzyme dosage. The results showed that prenatal exposure to VPA indeed induces ASD-like behaviors, including reduced sociability, increased repetitive behaviors, and impaired working memory.

Sholl analysis showed increased dendritic branching in granule and CA1 pyramidal neurons of VPA male mice, while VPA female mice exhibited hypoarborization in dentate gyrus granule cells. Both male and female VPA mice displayed higher dendritic spine density. Concurrently, oxidative stress was increased in the hippocampi of the VPA mice, as evidenced by alterations in oxidative stress biomarkers. Our work underscores gender differences in the effects of prenatal VPA exposure and points to a possible role for hippocampal neuron morphology and oxidative stress in the pathophysiology of ASD.