Gestational Valproate Exposure Induces Tissue-Specific Transcriptomic Changes in the Neonatal Brain and Choroid Plexus in a Rat Model of Epilepsy, GAERS

Valproate is an antiseizure drug required by many epileptic patients to manage their symptoms. During pregnancy, its use has been shown to increase the risk of neurobehavioral deficits in the offspring. The present study used a rat model of absence epilepsy, Genetic Absence Epilepsy Rat from Strasbourg (GAERS), to investigate the effects of gestational valproate exposure on early postnatal brain cortex and lateral choroid plexus transcriptomes. Females were provided with either a control diet or a valproate-laced diet (20 g/kg) from 2 weeks prior to mating and throughout gestation. At parturition, all dams received a control diet. Pups at Postnatal Day 5 were used for RNA sequencing. Differential expression analyses were conducted between transcriptomes from valproate-exposed and control animals. In the choroid plexus, 5694 genes significantly altered their expression compared to 214 in the cortex, a difference of nearly 25 times. Dysregulation was identified in choroidal expression of ion channels and metal transporters including six members of the Slc4a family, Cacna1h and Kcne2. Several drug transporting ATP-binding cassette transporters and solute carriers were significantly upregulated and drug-metabolising enzymes downregulated. In the cortex, 11 genes associated with the development of the central nervous system were differentially expressed. Finally, in both tissues, foetal valproate exposure appeared to result in dysregulation of genes related to adaptive and innate immune responses. These results indicated that gestational exposure to valproate resulted in distinct and greater effects on the choroid plexus transcriptome compared to the cortex, potentially suggesting additional targets related to developmental valproate neurotoxicity.