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A Model for the Pulsatile Secretion of Gonadotropin-Releasing Hormone from Synchronized Hypothalamic Neurons

Anmar Khadra ^* and Yue-Xian Li ^* 

Departments of ^* Mathematics and Zoology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z2

Correspondence: Address reprint requests to Yue-Xian Li, Depts. of Mathematics and Zoology, University of British Columbia, Rm. 121, 1984 Mathematics Road, Vancouver, BC, Canada V6T 1Z2. Tel.: 604-822-6225; Fax: 604-822-6074; E-mail: yxli{at}math.ubc.ca.

Cultured gonadotropin-releasing hormone (GnRH) neurons have been shown to express GnRH receptors. GnRH binding to its receptors activates three types of G-proteins at increasing doses. These G-proteins selectively activate or inhibit GnRH secretion by regulating the intracellular levels of Ca²⁺ and cAMP. Based on these recent observations, we build a model in which GnRH plays the roles of a feedback regulator and a diffusible synchronizing agent. We show that this GnRH-regulated GnRH-release mechanism is sufficient for generating pulsatile GnRH release. The model reproduces the observed effects of some key drugs that disturb the GnRH pulse generator in specific ways. Simulations of 100 heterogeneous neurons revealed that the synchronization mediated by a common pool of diffusible GnRH is robust. The population can generate synchronized pulsatile signals even when all the individual GnRH neurons oscillate at different amplitudes and peak at different times. These results suggest that the positive and negative effects of the autocrine regulation by GnRH on GnRH neurons are sufficient and robust in generating GnRH pulses.

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