DIRECT AND TRANSSYNAPTIC ACTIONS OF GNRH ON GNRH NEURONS - DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for the central neural regulation of reproduction. GnRH is released in discrete pulses in males and during most of the female reproductive cycle. To produce pulsatile release, the activity of scattered GnRH neurons must be coordinated. This is critical to fertility as prolonged constant GnRH release downregulates pituitary function, causing infertility. The sole physiological exception to pulsatile release is during the preovulatory period in females, when GnRH levels remain elevated for many hours in a GnRH surge, which is the neural prerequisite ovulation. The overall goal is to understand how GnRH neurons are coordinated to produce pulsatile release. The proposed work will focus on the role of GnRH itself in regulating a "GnRH responsive" local network that facilitates communication among GnRH neurons. GnRH is a signal unique to the reproductive neuroendocrine network and is thus a good candidate for within-network communication. Substantial evidence suggests the existence of such network. First, both axodendritic and axosomatic synapses exist between GnRH neurons. Second, GnRH receptor type 1 (GnRHRI) is expressed by a majority of GnRH neurons. Third, functional studies suggest GnRH neurons respond to GnRH. Interestingly, the dose response curve is biphasic, with low levels inhibiting and high levels stimulating GnRH neuronal firing. The cellular mechanisms for either inhibition or stimulation of native GnRH neurons by GnRH are not known. The basic neurobiological mechanisms and signaling pathways engaged by GnRH to bring about these changes will be examined using an electrophysiological approach. In Aim 1, the effects of GnRH on fast synaptic transmission to GnRH neurons will be examined. Preliminary data suggest such an indirect route using GABAergic interneurons may exist. In Aim 2, the direct effects of GnRH on ion conductances in GnRH neurons will be studied. Data from immortalized GnRH neurons have suggested different doses of GnRH may stabilize the interaction of different G-proteins with the GnRH receptor, suggesting a mechanism for the observed biphasic effect of GnRH on GnRH cell firing. In Aim 3, agonists and antagonists that respectively stimulate and suppress signaling through specific GnRH receptor-Gprotein combinations will be used with other pharmacological approaches to identify the signaling moieties utilized to initiate the different neurobiological mechanisms involved in GnRH control of the GnRH neuronal network. Together these data should provide novel insight into the production of pulsatile hormone release, and serve as the basis for developing new approaches to contraception and treatment of infertility.
