Project Summary Fetal Alcohol Spectrum Disorder (FASD) is a debilitating condition causing a wide range of disabilities including behavioral and intellectual deficits, facial dysmorphology, and organ malformations. This disorder has a profound impact on health care burden and cost; as many as 5% of children within the United States are affected by this condition, with lifetime treatment costs reaching $2 million per individual. Despite the severity of this disorder and its impact on public health, there currently are no therapeutic treatments available for FASD. As such, identifying therapeutic molecules that can alleviate neurobehavioral issues associated with FASD is critical. Our long-term objective is to identify effective treatments to ameliorate the cognitive impairments associated with FASD. We have recently discovered that the targeting of the KCNN2 potassium channel using a short peptide, Tamapin, improves both the gross and fine motor learning skills in our mouse model of FASD. These findings suggest that KCNN2 blockers have the potential to reverse the neurobehavioral problems associated with FASD and other neurodevelopmental disorders. We have already prescreened 6 peptide candidates from the 589 designs of Tamapin variants using in silico screening, and have custom-synthesized them. The goal of this STTR Phase I study is to select the lead drug candidate(s) that demonstrate the best performance in safely improving behavioral deficits in the mouse model of FASD. from the current 6 candidates. We will focus on in vitro screening of candidates through viability/cytotoxicity assays and in vitro electrophysiology analysis (Aim 1), and defining the in vivo efficacy of the lead peptides to improve neurobehavioral deficits in a mouse model of FASD (Aim 2). This research has immense potential in addressing the major public health issue of neurological deficits associated with FASD through identifying novel therapeutic peptides that may alleviate these symptoms.