Project Summary/Abstract Current anti-seizure medications are insufficient for managing seizures in epilepsy patients, as they become less effective over time and are associated with significant side effects. One promising molecular target for reducing seizures is the SUR1-TRPM4 channel. This channel is a sodium conducting ion channel not significantly expressed in healthy brain that upregulates de novo in neurons in other seizure-related disease pathologies such as stroke and traumatic brain injury. SUR1-TRPM4 upregulation is a disease-specific pathologic mechanism that has been successfully targeted and shown to be effective in reducing stroke pathology through preclinical studies and clinical trials. Preliminary data demonstrate that SUR1-TRPM4 expression increases in neurons in epileptic tissues resected from patients and in a pentylenetetrazol (PTZ) kindling rodent model of epilepsy. Furthermore, pharmacological inhibition of SUR1-TRPM4 in vitro prevents neuronal population hyperactivity induced by low Mg2+, and inhibiting SUR1-TRPM4 in vivo using pharmacologic inhibitors (glyburide, 9-phenanthrol) or genetic knock-out (KO) globally or specifically in neurons attenuates the development of seizures induced by PTZ kindling. This proposal aims to define the contributions of neuronal SUR1-TRPM4 expression to chronic seizure activity by assessing the effects of neuron-specific SUR1-TRPM4 overexpression on neuronal hyperexcitability in vitro and seizure susceptibility in vivo. This proposal fits the NINDS mission of reducing neurologic disease burden, has rapid translatable potential due to the SUR1 inhibitor glyburide being FDA approved, and could improve current anti-seizure medications by identifying a new epilepsy-specific therapeutic target not significantly expressed in healthy brain tissue. This research will be conducted across two labs with specific expertise in the SUR1-TRPM4 channel and epilepsy at a state-of-the-art institution in the University of Maryland School of Medicine. I will gain valuable experience in molecular and electrophysiologic techniques, particularly for inducing protein overexpression and data collection and analysis of neuronal firing via calcium imaging and electroencephalogram (EEG). Toward that end, this project will continue my development towards my ultimate career goal of becoming an independently funded neurosurgeon-scientist focused on translational and clinical research in epilepsy.