Fatty acid metabolism changes in association with neurobehavioral deficits in animal models of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) show behavioral problems due to prenatal alcohol exposure (PAE). A previous study reports changes in gene expressions linked to fatty acid (FA) metabolism in the cerebral cortex of the PAE mouse model. We find an increase of palmitic acid and arachidonic acid in phospholipid in the cerebral cortex of PAE at postnatal day 30. The increase of palmitic acid is consistent with increase of the producing enzyme, Fasn (fatty acid synthase). Decrease of 26:6 FA is also consistent with the increase of the enzyme which uses 26:6 as a substrate for making very long chain FAs, Elovl4 (elongation of very long chain fatty acids protein 4). However, there is no increase in the elongated products. Rather, lipid droplets (LDs) accumulated in the brain. Although FA-associated metabolic measurements are not affected by PAE, the abundance of FA-related gut microbiota is altered. This suggests that the gut microbiome could serve as a tool to facilitate uncovering the brain pathophysiology of FASD and a potential target to mitigate neurobehavioral problems.

Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders.

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.

Genome-wide profiling of differentially spliced mRNAs in human fetal cortical tissue exposed to alcohol.

Excessive alcohol consumption results in significant changes in gene expression and isoforms due to altered mRNA splicing. As such, an intriguing possibility is that disturbances in alternative splicing are involved in key pathological pathways triggered by alcohol exposure. However, no resources have been available to systematically analyze this possibility at a genome-wide scale. Here, we performed RNA sequencing of human fetal cortical slices that were obtained at the late first trimester and exposed to ethanol or control medium. We report 382 events that were identified as changes affecting the ratio of splicing isoforms in the ethanol-exposed fetal human cortex. Additionally, previously unreported novel isoforms of several genes were also identified. These results provide a broad perspective on the post-transcriptional regulatory network underlying ethanol-induced pathogenesis in the developing human cortex.