Cellular and molecular bases for rhythmic GnRH release

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DESCRIPTION (provided by applicant): Episodic release of gonadotropin-releasing hormone (GnRH) forms the final common pathway for the central regulation of reproduction. As such, understanding the mechanisms underlying this release has direct benefits to human health by providing new strategies for fertility and contraception in humans and in important food and fiber producing species. State-of-the-are electrophysiological approaches will be used to investigate the intrinsic and network properties that underlie episodic GnRH release in four specific aims. Aim 1 will examine the ionic conductances intrinsic to individual GnRH neurons that underlie initiation of action potential generation. How these conductances are modified over time in an individual neuron and how they change between reproductive state will be determined. Aim 2 will examine the voltage- and calcium-activated conductances induced by action potential firing in GnRH neurons. Differences in these conductances between action potential spikes and following the final action potential in a burst will be determined to address the question of how conductances change to stop firing of these cells. Aim 3 will test how GnRH neurons communicate with one another. Previous work shows that these neurons can use GnRH and glutamate as transmitters. The response to GnRH is dose-dependent with low doses inhibiting and high doses stimulating GnRH neuron activity. The signaling pathways underlying these differential responses will be tested with ligands that signal through specific GnRH receptor-Gprotein combinations. Chemical synaptic and electortonic coupling between GnRH neurons will be examined with dual recordings and the site of coordination explored. The fourth aim will explore interactions between GnRH neurons the local network in which they reside. Recent data indicate GnRH neurons not only release hormone to contol the downstream anterior pituitary, but also locally to regulate their GABAergic afferents. We wll explore other local network interactions with GABA and glutamate neurons, and with the astrocytes that ensheath GnRH neurons. A possible role for astrocytes in coordinating GnRH neuron activity will be addressed. Together these studies will provide insight into both the intrinsic and network properties leading to episodic GnRH release.