Valproic Acid Exposure During Gestation Alters Synaptic Plasticity 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 plasticity, and the expression of the Klotho protein in cognitive brain regions. Pregnant female mice were treated with VPA during gestation. Male offspring were subjected to behavioral tests assessing anxiety, sociability, and memory. Western blot assays were used to analyze synaptic markers, ELISA was performed to quantify soluble Klotho levels, and immunofluorescence was employed 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 altered synaptic excitability. Both ELISA and immunofluorescence analyses revealed a significant increase in Klotho expression in the frontal cortex, with no changes detected in the hippocampus or cerebellum. Gestational VPA exposure induces behavioral alterations consistent with an ASD-like phenotype and leads to region-specific changes in synaptic plasticity and Klotho expression. These findings suggest a possible role for Klotho in mediating adaptive or maladaptive responses to teratogenic insult and highlight its potential as a biomarker or therapeutic target in ASD-related conditions.