Prenatal alcohol (ethanol) exposure (PAE) significantly impacts cognitive and behavioral abilities of the
offspring. These conditions are defined as Fetal Alcohol Spectrum Disorders (FASD). Early intervention of
such abnormalities is imperative for optimal outcomes; however, specific therapeutic targets and effective
treatments are yet unavailable. The goal of this project is to elucidate the mechanisms underlying the long-term
impacts of prenatal alcohol exposure and find effective treatments for the symptoms caused by such impacts in
We have recently shown that the activation of heat shock signaling, which protects young neurons in
the alcohol-exposed embryonic brain, can instead cause neuronal migration delay when it is hyperactivated.
Our preliminary analysis has identified novel, long-term changes in gene expression associated with this
prenatal hyperactivation of heat shock signaling, at the single-cell level within the brains of adolescent mice.
These mice show gross and fine motor skills impairment, one of the earliest problems in FASD patients noticed
by caregivers. Some of these changes were negatively correlated with the motor learning ability of these mice,
and remarkably, reverting one of such altered factors, increased Kcnn2 (a calcium-activated potassium
channel) function, improved the motor learning deficits. In addition, preliminary data suggested that
overexpression of Kcnn2 in the motor cortex alone can cause motor learning defects.
Based on these findings and preliminary data, we hypothesize that epigenetic changes associated
with acute high-level activation of heat shock signaling in the fetal brain by PAE are involved in motor
learning defects in later life. To test this hypothesis, we will first define the postnatal epigenetic traits
specifically associated with the prenatal acute activation of heat shock signaling in the motor cortex of PAE
mice, which display motor learning deficits (Aim 1). By investigating the specific effects of Kcnn2
overexpression in untreated mice and those of Kcnn2 knockdown in PAE mice, we will then define how
increased Kcnn2 expression contributes to the learning deficits of PAE mice (Aim 2). We also test whether
reverting the increased Kcnn2 function can be a novel therapeutic target to improve the deficits (Aim 3). Our
multidisciplinary team puts our expertise to achieve these aims, by employing in vivo Kcnn2 manipulation, in
vivo imaging and behavior analysis (Torii lab.), electrophysiology and epigenetic analyses (Hashimoto-Torii
lab.). By combining a unique reporter system that we developed with these cutting-edge techniques, we will
uncover hitherto unknown epigenetic mechanisms leading to neurobehavioral problems in FASD, and develop
potentially novel interventions.