Abstract This project delves into the comprehensive study of the long-term neurobehavioral and cognitive impacts caused by Prenatal Alcohol Exposure (PAE), aiming to shed light on potential therapeutic targets for Fetal Alcohol Spectrum Disorders (FASD). During the previous funding period, crucial discoveries were made, particularly the correlation between elevated levels of the potassium channel KCNN2 in the motor cortex and motor learning deficits in PAE mice. Pharmacological interventions targeting KCNN2 showed promising improvements in these learning deficits. Further investigations revealed significant alterations in the expression of Apolipoprotein E (APOE) in both the cortex of PAE mice and the plasma of human PAE children. A specific single nucleotide polymorphism (SNP) in the enhancer of APOE was identified as a potential risk factor for cognitive deficits in human PAE subjects. Preliminary data suggested that postnatal administration of an APOE mimetic peptide could mitigate motor learning deficits in PAE mice, and this effect was associated with the restoration of KCNN2 levels, adjustments in NMDAR decay time, and reduced phosphorylation of CREB. The hypothesis of this project posits that dysregulated APOE expression in the brain contributes significantly to learning deficits observed in FASD, and that treatment with APOE mimetics can alleviate these deficits. To validate and further explore this hypothesis, the project is structured into three main objectives: 1. Understanding the underlying mechanisms leading to reduced APOE expression in the cortex of PAE mice; 2. Identifying how decreased APOE levels translate to learning and cognitive deficits in PAE mice; 3. Evaluating the effectiveness of APOE mimetic treatment in improving learning and cognitive abnormalities in PAE mice. Through this multifaceted approach, the project aims to contribute valuable insights to the field of neuroscience, specifically in understanding and potentially treating the neurobehavioral sequelae of PAE and FASD.