Reduction of excessive Kcnn2 activity ameliorates learning disability in the mouse model of Fetal Alcohol Spectrum Disorders

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. This is particularly true for patients suffering from Fetal Alcohol Spectrum Disorders (FASD) who exhibit a wide range of cognitive deficiencies including impaired motor skill development. While these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We have 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 lead to altered gene expression in their descendant neurons at the single-cell level. Among the altered genes, we found that an increase of the calcium-activated potassium channel Kcnn2 in subset neurons in the motor cortex correlates with motor skill learning deficits in the mouse model of FASD. We further show that postnatal blocking of Kcnn2 improves these learning deficits. These results propose Kcnn2 blockers as a novel intervention for learning disabilities in FASD and possibly for other neurocognitive conditions. Overall design: Total 28 samples were analyzed; 7, 15, and 5 replicates each for reporter-EtOH, reporter+EtOH, and reporter-PBS groups, respectively.