Valproic acid exposure during gestation alters synaptic markers and Klotho expression in the frontal cortex

Gestational exposure to valproic acid (VPA), a broad-spectrum antiepileptic drug, is associated with an increased risk of neurodevelopmental disorders, including symptoms resembling autism spectrum disorder (ASD). This study investigated the effects of VPA on behavior, synaptic markers, and Klotho protein expression in cognitive brain regions. Pregnant female mice were administered VPA during gestation. The male offspring underwent behavioral tests to assess anxiety, sociability, and memory. Western blot assays were used to analyze synaptic protein expression, ELISA was performed to quantify soluble Klotho levels, and immunofluorescence was used to evaluate its spatial distribution in cortical regions. VPA exposure resulted in increased anxiety-like behaviors, reduced sociability, and impaired aversive learning. PSD-95 levels were elevated in the frontal cortex, suggesting changes in the postsynaptic protein profile. ELISA and immunofluorescence analyses revealed a significant increase in Klotho expression in the frontal cortex, whereas no changes were detected in the hippocampus or cerebellum. Gestational VPA exposure induced behavioral alterations consistent with an ASD-like phenotype and produced region-specific changes in synaptic markers and Klotho expression. These findings suggest a possible role for Klotho in mediating adaptive or maladaptive responses to teratogenic insults and highlight its potential as a biomarker or therapeutic target in ASD-related conditions.