Neural and pituitary mechanisms linking epilepsy to co-morbid reproductive endocrine dysfunction

点击翻译按钮获取中文摘要

PROJECT SUMMARY Both men and women with temporal lobe epilepsy (TLE), the most common partial epilepsy in adults, exhibit higher rates of reproductive endocrine disorders compared to the general population. Reproductive endocrine disorders significantly impact quality of life and, if untreated, can result in elevated risks for other central nervous system, metabolic, and cardiovascular disorders, and cancer. Seizures appear to be major drivers of reproductive endocrine co-morbidities, but the neural mechanisms underlying this relationship have not been described. In the proposed work, we will elucidate neural mechanisms that link epilepsy to reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons form the final common pathway in the brain's control of reproduction and thus likely play critical roles in the pathophysiology of epilepsy-associated reproductive endocrine disorders. Proper GnRH release patterns are necessary to drive pulsatile luteinizing hormone (LH) release from the pituitary gland in both males and females. Clinical studies have reported disrupted patterns of LH release in men and women with epilepsy, but the mechanistic underpinnings have yet to be elucidated. A major gap in knowledge thus exists about the effects of epilepsy on GnRH neurons, their synaptic afferents, and downstream impacts on pituitary function. Our overall objectives in the proposed studies are to determine key functional changes in hypothalamic-pituitary cells and circuits in a mouse model of TLE. We recently reported that female estrous cyclicity is disrupted in most epileptic female mice in this model, indicating that it is appropriate for these studies. Our central hypothesis is that seizure activity drives changes in the activity of GnRH neurons and their synaptic inputs, thereby impacting downstream pituitary LH release. We will test this hypothesis using an innovative combination of patch clamp electrophysiology, electroencephalography (EEG), optogenetics, pituitary gene expression analysis, and a cutting-edge ultrasensitive assay for determining mouse LH release patterns in vivo. In Aim 1 we will perform the first direct investigations of epilepsy-associated changes in GnRH neuron firing activity, intrinsic excitability, and fast synaptic inputs. In Aim 2 we will determine the functional relationships between hippocampal seizure activity, hypothalamic GnRH release, and pituitary response to GnRH. Successful completion of these Aims will have positive translational impact and further the goals of the NINDS Epilepsy Research Benchmarks by providing key mechanistic insights into the underlying neural and pituitary substrates of reproductive endocrine disorders that commonly arise with epilepsy.