Central Control of Reproduction: Mechanisms of Kisspeptin Actions on Gonadotropin-releasing Hormone Neurons: Intrinsic, Network Properties and Their Sensitivity to Estradiol

Gonadotropin-releasing hormone (GnRH) neurons centrally control reproduction. A distinct pattern of GnRH release is required for secretion of gonadotropic hormones from the pituitary. Gonadotropins, in turn, promote gametogenesis and steroid production by the gonads. Steroids feed back to regulate GnRH release. Understanding GnRH neuron function is indispensable to find treatments for people with fertility abnormalities. An example of such a disorder is hypogonadotropic hypogonadism (HH). Patients with HH are infertile, and this is likely due to an abnormal pattern of GnRH release. Many of these patients carry mutations in G-protein-coupled receptor 54 (GPR54). A great deal of work has been done on the role of GPR54 and its ligand kisspeptin in reproduction; however, the mechanisms of kisspeptin action are not well understood. GnRH neurons express GPR54, suggesting direct actions of kisspeptin; however, GPR54 is also expressed in other parts of the brain, suggesting indirect actions are possible. This dissertation investigated the effects of kisspeptin on the intrinsic and synaptic properties of GnRH neurons and its potential role in estradiol feedback regulation of GnRH activity. First, we showed that kisspeptin utilizes direct and indirect mechanisms to increase GnRH neuron activity. Estradiol potentiated the GnRH response to kisspeptin via transsynaptic mechanisms. The direct effect of kisspeptin was not estradiol-sensitive and involved alterations in potassium conductances. Second, we investigated the transsynaptic mechanisms kisspeptin uses to increase GnRH neuron activity. Our data showed that estradiol enabled kisspeptin to increase GABA and glutamate transmission to GnRH neurons and postsynaptic responses to GABA. Third, we studied the direct mechanism of kisspeptin action by looking at its effect on voltagegated potassium currents in GnRH neurons. We also examined the role of these channels in estradiol positive/negative feedback regulation of GnRH neurons. We found that kisspeptin excites GnRH activity by reducing the transient component of voltagegated potassium currents. Additionally, we demonstrated that voltage-gated potassium conductances are targets of estradiol feedback regulation of GnRH neuronal activity. Altogether, this work provides novel findings about the mechanisms responsible for the stimulatory effects of kisspeptin on GnRH neuronal activity, as well as its role in estradiol feedback regulation of GnRH secretion.