A novel target for seizure suppression in chronic temporal lobe epilepsy

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Project Summary/Abstract Over 1 million Americans suffer from temporal lobe epilepsy. Unfortunately, one third of those individuals suffer from uncontrolled, medically refractory, seizures. In addition to diminishing one’s quality of life, uncontrolled seizures also greatly increase the risk of sudden death from epilepsy. The development of new treatment options that reach a wider patient population will reduce the number of people suffering from uncontrolled seizures. An important step in developing new treatments for temporal lobe epilepsy is to understand the underlying neural circuitry of the effected region. Most often in temporal lobe epilepsy, the seizure focus is the hippocampus. The current project will explore how an inhibitory cell population with little prior characterization in the literature fits into the healthy and epileptic hippocampal circuitry. Furthermore, this project may identify a candidate target for the development of novel and efficacious treatment options for people with medically refractory temporal lobe epilepsy. Specifically, this project aims to examine a cell population hereby referred to as LINCs (or, long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells). First, in a mouse model of chronic temporal lobe epilepsy, I will test the hypothesis that LINCs are a cohesive cell population that provide strong, long-lasting, and widespread inhibition to the healthy and epileptic hippocampus. Then, using an on-demand optogenetic seizure intervention strategy previously developed by my advisor and sponsor Dr. Krook-Magnuson, I will test the hypothesis that LINCs are capable of reducing seizure duration, frequency, and severity. The results of this project will increase our knowledge of healthy hippocampal circuitry and will illustrate how that circuitry is altered in the epileptic brain. Additionally, the results of this study may identify a novel target for the development of new anti-seizure therapeutics. Through the training proposed here, I will gain the tools necessary to investigate neurological disorders at a cellular and circuit level and will be well-prepared to take the next steps towards a career as an independent scientist.