Transcriptome Analysis and Epigenetics Regulation in the Hippocampus and the Prefrontal Cortex of VPA-Induced Rat Model

Abstract

Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders caused by complex interaction between various genes and environmental factors. As the hippocampus and prefrontal cortex are involved in social recognition, they are the regions of the brain implicated in autism. The effects of prenatal exposure to valproic acid (VPA) can induce an ASD phenotype in both humans and rats; this tool is commonly used to model the complexity of ASD symptoms in the laboratory. However, researchers rarely undertake epigenetic regulation of the brain regions using this model. The present study has addressed this gap by examining gene expression abnormalities in the hippocampus and prefrontal cortex in the VPA rat model of ASD. mRNA and miRNA sequencing was performed on samples from the hippocampus and prefrontal cortex of the VPA model of autism. According to the analysis, 3000 mRNAs in the hippocampus and 2187 mRNAs in the prefrontal cortex showed a significant difference in expression between the VPA and saline groups. In addition, there were 115 DE miRNAs in the hippocampus and 14 DE miRNAs in the prefrontal cortex. Further, the predicted and validated target mRNA of DE miRNA enriched pathways involved neurotransmitter uptake, long-term synaptic depression, and AMPA receptor complex (anti-GluA2-b) in the hippocampus; as well as the neuroactive ligand-receptor interaction and regulation of postsynaptic membrane potential in the prefrontal cortex. This revealed the negative regulation network of miRNAs-mRNAs in the hippocampus and prefrontal cortex, while filtering out key genes (miR-10a-5p and Grm3). Finally, the significant variable miR-10a-5p and its negative regulated genes (Grm3) were verified in both brain regions by QPCR. Importantly, the fact that miR-10a-5p downregulated Grm3 in both the hippocampus and the prefrontal cortex may play a potentially significant role in the occurrence and development of autism. This study suggests that the VPA model has the potential to reproduce ASD-related hippocampus and prefrontal cortex abnormalities, at the epigenetic and transcriptional levels. Furthermore, the network of miRNAs-mRNAs was confirmed; this negative regulatory relationship may play a key role in determining the occurrence and development of autism. The study of this topic help better understand the pathogenesis of ASD.

Keywords: Autism; Grm3; Transcriptome; miRNA.