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

This animal study looked at how a medication called valproic acid affects brain development when exposure occurs before or after birth. The researchers found that exposure before birth caused more severe and lasting brain changes, including problems with brain cell movement and growth factors that help neurons develop. Exposure after birth caused temporary changes. Both types of exposure created imbalances in different brain regions that are important for autism-related behaviors.

This preclinical study investigated how valproic acid (VPA) exposure during prenatal and postnatal periods affects brain development in an autism model. Researchers examined molecular changes in key brain regions at two developmental timepoints, measuring neurotrophins and neurogenesis markers. Prenatal VPA exposure caused more severe and persistent disruptions, including reduced BDNF in the subventricular zone and impaired cell migration markers. Postnatal exposure led to transient changes with delayed growth factor production.

Both exposures created region-specific imbalances between neurons and glial cells, with structural changes including ventricular wall thickening. The findings demonstrate stage-dependent vulnerability during brain development and highlight critical periods when VPA exposure poses greatest risk for neurodevelopmental disruptions associated with autism spectrum disorders.

Findings emphasize the importance of minimizing VPA exposure during late pregnancy and early postnatal periods. Results support current clinical recommendations for avoiding VPA in pregnant women when possible, and highlight the need for careful monitoring and alternative treatments during critical neurodevelopmental windows.

This is a preclinical animal study, limiting direct translation to humans. Sample size was not reported, making it difficult to assess statistical power. The study examined only two developmental timepoints, potentially missing other critical periods of vulnerability.

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.