Mouse model of prenatal valproic acid exposure: Effects on cortical morphogenesis and behavioral outcomes across environmental conditions

Abstract

Autism spectrum disorder is a developmental disability characterized by impaired social communication and repetitive behaviors, and environmental and genetic factors are involved in its onset. The use of the antiepileptic drug valproic acid (VPA) during pregnancy is associated with neural tube defects and developmental disorders in the fetus. In this study, we aimed to identify abnormalities in cortical morphogenesis owing to prenatal VPA exposure and to elucidate the abnormalities in brain function associated with these abnormalities, particularly by comparing multiple and single environments. Pregnant mice were administered a single dose of 400 mg/kg/day of VPA on embryonic day 12, and the morphogenesis and behavioral characteristics of the fetal and newborn mouse brains were analyzed. Prenatal VPA exposure caused an increase in cell proliferation and morphological abnormalities in microglia. In the single-housing environment, a decrease in spontaneous locomotor activity and psychomotor activity, and an increase in anxiety-like behavior and abnormal social interactions, were observed. In the multiple-housing environment, no effect on spontaneous activity was detected, however, an effect on social interactions and social proximity was observed. These findings provide valuable insights into the effects of environmental factors during the fetal period on the risk of developmental disorders. Moreover, they indicate that developmental disorder-like behavior is also affected by the environment.