PROJECT SUMMARY/ABSTRACT Epilepsy is frequently associated with Alzheimer's Disease (AD), but whether there are shared common mechanisms is largely unknown. Network hyperactivity due to altered functional connectivity of GABAergic interneurons is believed to underlie many cognitive disorders and a “disease of interneurons” is the major hypothesis for epilepsy. However, little is known about the pathophysiology of interneurons particularly in patients with Apo4-associated AD and epilepsy. Understanding the role of ApoE4 in interneuron dysfunction requires direct investigation of interneuron properties in human neurons derived from patients with these mutations. Reprogramming patient somatic cells enables recapitulation of normal and pathological human tissue developmental properties in defined conditions and a new way to identify the cellular processes underlying complex human diseases, which can lead to mechanism-based drug discovery. Aim 1 will test the hypothesis that ApoE4 will cause degeneration of GABAergic neurons in 3D cortical spheroids which is associated with AD-related pathology by labeling spheroids with a Dlx1/2-GFP reporter to monitor interneuron behavior and correlating these cellular changes with AD-related pathology. Aim 2 will test the hypothesis that ApoE4-dependent degeneration will lead to hyperexcitability in 3D cortical spheroids by performing multi-electrode array recordings to measure baseline neural activity and after exposure with different anti-seizure drugs. Together, these studies are expected to provide a greater understanding of how ApoE4 functions in human cortical interneuron development and function at the network level, therefore contributing to the understanding of the pathophysiology of AD, which could help uncover new strategies to treat patients with AD and epilepsy.