The search for a fetal origin for autism: Evidence of aberrant brain development in a rat model of autism produced by prenatal exposure to valproate

Abstract

A variety of animal models for autism have been used to investigate autism, including models based on genetic manipulation (knockout) of candidate genes, and surgical lesions to specific brain regions. Most of these models have focused on the study of abnormalities observed in adult animals. We considered that the study of abnormalities at a fetal level might provide information concerning mechanisms underlying early developmental alterations that give rise to autism. For example, prenatal exposure to chemicals such as Valproate (VPA) has been clinically associated with an increased risk of autism in humans. Exposing pregnant rats to VPA has been reported to induce several behavioral and neurochemical anomalies associated with autism in offspring. Here, we have focused on developmental changes in fetal rat brains shortly after VPA exposure. We treated pregnant Sprague Dawley rats with VPA orally on gestation day 9 or 11, and observed different brain regions at embryonic day 16. VPA treatment on either day impaired development of the cortical plate in the cerebral cortex. We also detected an abnormal formation of nerve tracts and impaired migration and distribution of aminergic neurons in the hindbrain. These results suggest that the VPA-induced animal model of autism can reproduce, at least in part, some anatomopathological findings reported in idiopathic autism, and that such changes are already apparent in the fetal brain.