Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Abstract

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy, moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNAseq data ob-tained from fetal mouse brains 3 hr after VPA administration revealed that VPA significantly [p(FDR) ≤ 0.025] increased or decreased the expression of approximately 7,300 genes. No significant sex dif-ferences in VPA-induced gene expression were observed. Expression of genes associated with neurodevelopmental disorders such as autism as well as neurogenesis, axon growth and synapto-genesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 400 autism risk genes was significantly altered by VPA. In addition, expression of 247 genes that have been reported to play fundamental roles in the development of the nervous system, but are not linked to autism by GWAS, was significantly increased or decreased by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria provides potential targets for future hypothesis-driven approaches to elucidating the proximal underlying causes of defective brain connectivity in neuro-developmental disorders such as autism.

Characterization of Social and Repetitive Behaviors ofMllt11/Af1q/TcF7cConditional Knockout Mice

“…Differences in cortical thickness, likewise, are shared among at least 6 common NDDs 21,26,27 . Mllt11 has also been found to be dysregulated in fetal mice following maternal Valproic Acid (VPA) administration -a common mouse model used to study ASD 28,29 . Given that Mllt11 cKO mouse brains share histological abnormalities with individuals with NDDs, its dysregulation following VPA, and the CNV of the region containing Mllt11 in an ASD patient, we hypothesized that Mllt11 loss of function in our Cux2 iresCre -driven Mllt11 cKO mice would display ASD behavioral symptomology.…”