Summary Huntington's Disease (HD) is a neurodegenerative disease that is characterized by progressive impairments of motor and cognitive functions, leading to uncontrolled movements (chorea), dementia and reduced life expectancy. An inherited mutation in the Huntington protein (Htt) underlies HD, leading to intracellular accumulation and aggregation, with extensive neurodegeneration in the basal ganglia, specifically GABAergic medium spiny neurons (MSNs). There are currently no treatments for HD. Recent studies have focused on the role of astrocytes in HD. In particular, the inwardly-rectifying potassium channel Kir4.1 is downregulated in striatal astrocytes of mice with HD, leading to hyperexcitability of MSN neurons. EEAT2 expression and function are also impaired in HD mice. We hypothesize that a selective small molecule Kir4.1 activator could enhance endogenous Kir4.1 activity, and potentially lead to a novel treatment for HD. To address this, we propose to (1) identify new small molecule pharmacophores of Kir4.1 channels using an innovative approach of virtual screening and unique modulatory sites in Kir4.1 channels, and (2) assess the effect of these small molecule Kir4.1 pharmacophores on an astrocytic-neuronal function and HD mice. These experiments will provide the foundation for new studies probing the role of Kir4.1 in HD.