GABAergic mediation of steroid feedback on GnRH neurons

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Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway regulating reproduction. Pulsatile GnRH release from the hypothalamus stimulates synthesis and secretion of pituitary gonadotropins and is absolutely required for fertility. GnRH pulse patterns are largely regulated by negative feedback from the ovarian steroids estrogen (E) and progesterone (P). Evidence suggests one mechanism of steroid hormone feedback is via interneurons to modulate GnRH pulsatility transsynaptically. Anatomical and physiological data support a role for gamma-aminobutyric acid (GABA)-producing neurons in this communication. The goal of this study is to characterize GABA/A-receptor-mediated inhibitory post-synaptic currents (IPSCs) within GnRH neurons and their modulation by steroids and neurosteroids. Specifically, whole-cell voltage clamp techniques will be used to characterize IPSCs in three defined mouse models of steroid hormone feedback. Based on reports of decreased GnRH neuron response to steroid negative feedback in some hypothalamic fertility disorders, IPSCs will also be characterized in an animal model that recapitulates reduced responsiveness to steroid feedback, IPSCs will also be characterized in an animal model that recapitulates reduced responsiveness to steroid feedback. Molecular analyses of GABAA receptor subunit expression within GnRH neurons and changes in hypothalamic levels of enzymes involved in the production of neuroactive steroids will complete these data. The absolute requirement for proper regulation of GnRH pulsatility for fertility underscores the importance of the proposed research.