Table 6.

Changes in brain gene expression induced by prenatal or early postnatal VPA.

Authors, Ref Number	Description	Findings
Weinstein—Fudim et al. [161]	Nanostring nCounter analysis of 770 neuropathology and neurophysiology genes in the prefrontal cortex of offspring postnatally treated with 300 mg/Kg VPA on PND 4.	VPA induced changes in gene expression in a sex-dependent manner, with more genes changed in females. Gene enrichment in pathways related to Huntington’s disease, Alzheimer’s disease, prostate cancer, focal adhesion and calcium and PIK3-signaling.
Weinstein—Fudim, et al. [173]	Nanostring nCounter analysis of 770 neuropathology and neurophysiology genes in the one-day-old newborn pup forebrain, after prenatal exposure to 300 mg/kg of VPA on day 12 of gestation.	No significant changes in gene expression were found.
Lenart et al. [165]	A total of 99 genes related to excitatory glutamatergic and inhibitory GABAergic pathways in cerebral cortex, hippocampus and cerebellum from Wistar rats prenatally exposed to VPA.	Genes encoding the presynaptic glutamatergic proteins vGluT1 and mGluR7 and PKA were elevated more than 100-fold, mostly in the frontal cerebral cortex. Gene expression changes related to GABAergic pathways were relatively small in all three brain areas.
Kotajima-Murakami, et al. [159]	Whole mouse genome was investigated by microarray analysis in the brains of adolescent male mice prenatally exposed on day 12.5 to 600 mg/kg VPA.	Among differentially expressed genes in the brain, 2761 genes were upregulated, and 2883 were downregulated. Differentially expressed genes by VPA were associated with the mTOR (mammalian target of rapamycin) signaling pathway.
Feleke et al. [166]	Genome-wide gene expression analysis of 21-day fetuses brains from epileptic (Genetic Absence Epilepsy Rats from Strasbourg) and non-epileptic control rats.	VPA induced an altered pattern of gene expression independent of the genetic epilepsy background. Differentially expressed genes were related to synaptic function and neuronal processes (glutamate receptor complex and neurotransmitter receptor activity and regulation of insulin secretion).
Zhang et al. [167]	Whole transcriptome sequencing of the prefrontal cortex in adolescent male rats exposed to 600 mg/kg VPA on gestation day 12.5.	A total of 3228 genes were differentially expressed, with 637 genes exhibiting alternative splicing. The changes were associated with genes associated with Huntington’s, Alzheimer’s, and Parkinson’s diseases and associated with pathways related to neurogenesis.
Huang et al. [168]	Microarray analysis of 721 genes in 50-day-old male rats hippocampus exposed to 600 mg/kg VPA on gestational day 12.5.	Most differently expressed genes were downregulated. These genes were associated with the plasma membrane, G-protein signaling, amine binding and calcium signaling.
Guerra et al. [169]	Gene expression analysis in PND1, PND10 and PND30 cerebellum of C57Bl/6 male mice prenatally exposed to VPA.	Differentially expressed genes of six different clusters demonstrated progressive or regressive patterns of gene expression during the different stages of postnatal cerebellar development. Genes were related to synaptic functions or neurogenesis. They were associated with ASD-related genes overlapping with 159 developmentally regulated genes appearing in either the SFARI database or/and the Autism Gene Database (AutDB).