31593
Valproic Acid Induced Expression Changes in Developing Cortical Neurons Provide Genetic Link to Autism Risk
Both genetic and environmental factors have been associated with increased risk for autism spectrum disorder (ASD). Large-scale genomic projects have, in recent years, progressively increased our knowledge of the genetic architecture of ASD as well as provided biological and mechanistic insights. However, we are still far from understanding the interplay between genetic and environmental risk factors and how this affect brain development.
Valproic acid (VPA) is a commonly used anti-convulsive drug used in the treatment of epileptic seizures. Prenatal exposure to VPA is associated with increased risk of congenital malformations, intellectual disability (ID), ASD and attention deficiency and hypersensitivity disorder (ADHD). Mice and rats prenatally exposed to VPA show behavioral changes with translational relevance to ASD and evidence points towards VPA causing an imbalance of excitatory and inhibitory neurons.
VPA is a broad histone deacetylase (HDAC) inhibitor with high affinity for HDAC1 and 2 and its actions cause epigenetic- and gene expression changes in cells. The HDACi 4b is a selective class I HDAC inhibitor with high affinity to HDAC 3 compared to HDAC1 and 2.
Objectives:
We hypothesized that prenatal exposure to VPA will dysregulate the expression of ASD risk genes in the brain. Considering, that known rare and de novo ASD risk variants are typically disruptive of protein function, we hypothesized that VPA would decrease the expression of these genes.
Methods:
To investigate these hypotheses, we exposed developing, primary cortical neuron cultures from newborn mice to vehicle, VPA and HDACi 4b, and examined temporal neurite formation, neuronal markers and comparative transcriptomic expression profiles. We integrated our transcriptomic data with data from large psychiatric genomic studies and functional gene sets with relevance to mental illness and performed enrichment analyses.
Results:
Our analyses revealed a comprehensive downregulation of rare and de novo variant ASD risk genes as well as enrichment of common variant ASD risk genes following VPA exposure. VPA also dysregulated genes associated with ID, FMRP targets and other gene sets implicated with mental illnesses.
Conclusions:
Valproic acid decrease the expression of rare and de novo variants ASD risk genes in primary cortical neurons providing a direct link between environmental and genetic risk for ASD. In support, we observed a significant dysregulation of common variant ASD risk genes in cultures exposed to VPA. HDACi 4b did not show the same effects on ASD risk genes, suggesting that inhibition of HDAC1 and 2, but not HDAC3, affects the expression of ASD risk genes.