Rescue of ethanol-induced FASD-like phenotypes via prenatal co-administration of choline

Abstract

Maternal consumption of alcohol during pregnancy can generate a multitude of deficits in the offspring. Fetal Alcohol Spectrum Disorders, or FASD, describe a palette of potentially life-long phenotypes that result from exposure to ethanol during human gestation. There is no cure for FASD and cognitive-behavioral therapies typically have low success rates, especially in severe cases. The neocortex, responsible for complex cognitive and behavioral function, is altered by prenatal ethanol exposure (PrEE). Supplementation with choline, an essential nutrient, during the prenatal ethanol insult has been associated with a reduction of negative outcomes associated with PrEE. However, choline's ability to prevent deficits within the developing neocortex, as well as the underlying mechanisms, remain unclear. Here, we exposed pregnant mice to 25% ethanol in addition to a 642 mg/L choline chloride supplement throughout gestation to determine the impact of choline supplementation on neocortical and behavioral development in ethanol-exposed offspring. We found that concurrent choline supplementation prevented gross developmental abnormalities associated with PrEE including reduced body weight, brain weight, and cortical length as well as partially ameliorated PrEE-induced abnormalities in intraneocortical circuitry. Additionally, choline supplementation prevented altered expression of RZRβ and Id2, two genes implicated in postmitotic patterning of neocortex, and global DNA hypomethylation within developing neocortex. Lastly, choline supplementation prevented sensorimotor behavioral dysfunction and partially ameliorated increased anxiety-like behavior observed in PrEE mice, as assessed by the Suok and Ledge tests. Our results suggest that choline supplementation may represent a potent preventative measure for the adverse outcomes associated with PrEE.