A novel inhibitory target for temporal lobe epilepsy

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ABSTRACT Temporal lobe epilepsy is the most common form of epilepsy in adults, and new treatment options are needed. Using viral vectors and intersectional genetic approaches in transgenic mice, we are able to selectively label and manipulate a unique subpopulation of NOS-expressing inhibitory neurons (referred to in this proposal as “NPINs”) which our preliminary data indicate may be excellent targets for intervention in temporal lobe epilepsy. The experiments outlined in this proposal provide a basic characterization of NPINs in healthy and epileptic animals, and test the hypothesis that on-demand optogenetic activation of NPINs will inhibit seizures in a mouse model of temporal lobe epilepsy. Investigation of neuronal circuits and their constituent cell-types improves our understanding of neurological disorders including epilepsy, and allows for the informed design of new treatment options. Our preliminary data indicate that NPINs provide inhibition within the hippocampus and have extrahippocampal projections, including to the frontal cortex. Within the hippocampus, our preliminary data shows that NPINs provide strong, broad, and long lasting inhibition, placing NPINs in an ideal position to alter network activity. Oscillatory activity, including theta, plays an important role in hippocampal physiology, and coherent oscillations are important for coordinated information transfer and predict task performance. Our preliminary data indicates that NPINs are able to induce theta oscillations preferentially, and we further hypothesize that NPINs will increase the coherence of theta within the hippocampus and between the hippocampus and frontal cortex in healthy animals. Importantly, NPINs’ apparent ability to provide broad and strong inhibition also suggests that on- demand optogenetic activation of NPINs may be an effective strategy to inhibit seizures in chronically epileptic animals. Further supporting this strategy, our preliminary data demonstrates that in chronically epileptic animals NPINs persist despite a reduction in overall number and continue to provide strong inhibition. Taken together, our preliminary data indicates that NPINs are a unique neuronal population poised to have a major impact on hippocampal activity. By exploring NPINs in health and in epilepsy, the experiments outlined in this proposal will provide a fuller account of hippocampal cell types and circuitry, including GABAergic projection neurons, and improve our understanding and ability to treat disorders including epilepsy. Given their ability to provide broad and strong inhibition, NPINs are exciting as a possible therapeutic target in temporal lobe epilepsy.