Stage-Dependent Disruptions in Neurogenesis and Neurotrophins’ Production Following Prenatal and Postnatal Valproic Acid Exposure: Implications for Autism Spectrum Disorders

Autism spectrum disorders (ASD) are neurodevelopmental conditions involving impaired neuronal processes such as connectivity, synaptogenesis, and migration. Prenatal exposure to valproic acid (VPA), an anticonvulsant and mood stabilizer, is linked to increased ASD risk, with timing as a key factor. However, the molecular mechanisms of VPA-induced neurodevelopmental disruptions remain unclear. Building on our previous study, which characterized VPA-induced prenatal and postnatal ASD models with impaired social behavior, repetitive patterns, and altered brain connectivity, this study examines molecular changes in neurogenic brain regions. We analyzed the prefrontal cortex, hippocampus, and subventricular zone at key developmental time points (postnatal days 14 and 21), assessing neurotrophins (BDNF, Nt-3, IGF-β, GDNF) and markers of cell migration (DCX), differentiation (NeuN, GFAP), and synaptogenesis (synaptophysin). Our findings show that both prenatal and postnatal VPA exposure disrupt neurogenesis, with prenatal effects being more severe and persistent. Prenatal VPA significantly reduced BDNF in the subventricular zone and DCX in the olfactory bulb, suggesting impaired migration, while morphological analysis revealed thickening of ventricular lateral wall and disrupted cellular organization. Postnatal exposure led to transient neurotrophin changes, including delayed IGF-β production and an abnormal rise of BDNF levels. Elevated GFAP and reduced NeuN or synaptophysin in the prefrontal cortex, alongside increased neuronal markers in the hippocampus, suggest region-specific neuroglial imbalances. These findings highlight the stage-dependent vulnerability of the developing brain to VPA exposure, revealing distinct mechanisms of disruption in prenatal and postnatal administration. They underscore the need to minimize exposure risks during late gestation and early postnatal periods, which are crucial for neurodevelopment.