Despite numerous advances in epilepsy therapeutics, seizures refractory to medical intervention remain a significant cause of morbidity and disability in patients with epilepsy. Longitudinal studies involving patients with epilepsy have shown reduction of frequency and severity of seizures in many patients, but both surgically and medically treated patients often demonstrate a progressive decline in memory function despite treatment. As such novel approaches to controlling seizures in epilepsy are warranted. Increased seizure propensity in epilepsy is caused by abnormal neuronal excitability. Voltage gated ion channels play an important role in controlling intrinsic neuronal excitability, and many have been implicated in human and animal epilepsy syndromes. One such class of voltage-gated ion channels is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, which mediates the cationic current, Ih. Four closely related genes (Hcn1-4) coding for distinct channel subunit proteins (HCN1-4) have been identified;these channels have been implicated in both generalized and focal epilepsies. Global deletion of Hcn2 causes absence epilepsy in mice, likely by increasing calcium channel bursting in thalamocortical neurons. We have recently characterized a novel spontaneous mouse neurological mutant, apathetic, which has absence epilepsy owing to a four base pair insertion in the Hcn2 gene that disrupts HCN2 protein expression. Because loss of HCN2 in thalamocortical neurons produces calcium channel-mediated bursting that leads to absence seizures in mice, we hypothesize that viral overexpression of HCN2 in thalamocortical neurons will restore normal h channel function and reduce seizures in the epileptic, apathetic mice. We will utilize physiological, cell biological and biochemical techniques to address the following specific aims: 1) To determine whether viral overexpression of HCN2 in thalamocortical neurons of apathetic mice can restore HCN2 protein expression and reverse the deficit in Ih, and 2) to determine whether viral overexpression of HCN2 in thalamocortical neurons reduce seizures in apathetic mice. PUBLIC HEALTH RELEVANCE: With respect to public health, despite numerous new medical and surgical treatments, refractory seizures remain a significant cause of disability in patients with epilepsy. The purpose of this work is to explore whether gene therapy utilizing viral delivery of specific ion channel genes to neurons can effectively reverse ion channel deficits and prevent seizures in epileptic brain, with the ultimate goal of exploring this tool as a novel therapy for medically refractory epilepsy.