Epilepsy-Associated Dysfunction in the Kisspeptin-GnRH Neural Circuit

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PROJECT SUMMARY Patients with temporal lobe epilepsy (TLE), the most commonly diagnosed form of focal epilepsy in adults, have been shown to experience reproductive endocrine disorders at a rate higher than the general population. Notably, clinical studies have also found disrupted patterns of luteinizing hormone (LH) release in both sexes. Gonadotropin-releasing hormone (GnRH) neurons form the final common output in the brain’s control of reproduction, and they play a key role in the pituitary release of LH. Our lab has shown that both GnRH neuron firing activity and intrinsic excitability are disrupted in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Upstream kisspeptin neuron populations in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are major sources of synaptic transmission to GnRH neurons. ARC kisspeptin neurons play a key role in the pulsatile release of LH in both sexes, and AVPV kisspeptin neurons regulate the preovulatory GnRH/LH surge in females. However, kisspeptin neuron function has never been studied in an animal model of epilepsy. Thus, there is a gap in knowledge regarding the effects of epilepsy on the hypothalamic kisspeptin- GnRH circuit. The overall objective of this specific proposal is to elucidate epilepsy-associated changes in the kisspeptin-GnRH circuit. In Aim 1, patch clamp electrophysiology will be employed to determine epilepsy-induced changes in kisspeptin neuron function and excitability in relation to estrous cycle stage and sex. A combination of whole-cell current clamp and loose-patch recordings will be used to analyze epilepsy-associated changes in kisspeptin neuron intrinsic excitability and firing activity. In Aim 2, two-photon calcium imaging will be conducted to identify epilepsy-associated changes in GnRH neuron axon terminal activity and response to kisspeptin. Completion of these aims will provide the foundational information necessary to make continued progress towards the NINDS Epilepsy Research Benchmarks of controlling epilepsy-related conditions and preventing the adverse consequences of seizure treatment. The training plan contained within this proposal seeks to facilitate the development of the primary investigator to better prepare him for a career as an independent researcher. This training plan places heavy emphasis on laboratory-based learning, with small amounts of additional classroom-based learning also included to provide the conceptual foundation needed for the technical training. This research experience will also take place in an intellectual environment that allows for the prioritization of those experiences that will play key roles in the development of the primary investigator.