Prenatal valproate exposure alters midbrain and striatal neuronal morphology along with dopamine levels

Alterations in dopaminergic pathways are implicated in the pathogenesis of neuropsychiatric disorders, including autism spectrum disorder (ASD). However, changes in morphology and neurite outgrowth within the dopaminergic system under autism-relevant conditions remain poorly understood. Prenatal valproate (VPA) administration is a well-established animal model for studying autism-related brain changes in offspring. Therefore, the aim of this study was to examine the effects of prenatal VPA exposure on (1) the morphology of primary neurons isolated from dopaminergic brain regions, and (2) the expression of molecular motors and neurite outgrowth-related proteins, along with (3) the levels of dopamine and dopamine receptors in the midbrain and striatum, analysed at postnatal day 30 (P30). Neurons from the ventral tegmental area (VTA) of rats prenatally exposed to VPA showed a significant reduction in both the number and length of neurites. Similar, but to a lesser extent, changes were also found in primary striatal tyrosine hydroxylase (TH)-positive neurons, compared to controls. A significant increase in total dopamine levels was observed in the midbrain of rats prenatally exposed to VPA, regardless of sex, while no significant changes were detected in the striatum at P30. TH levels were unchanged in dopaminergic regions at P30, while dopamine receptor type 4 gene expression was significantly increased in the VTA of prenatally VPA-exposed male rats, with no other significant gene expression changes. These results demonstrate that prenatal VPA exposure induces region-specific neuronal and dopaminergic changes in the midbrain and striatum, enhancing our understanding of the neurodevelopmental mechanisms potentially underlying ASD-like symptomatology.