How Pulsatile Kisspeptin Stimulation and GnRH Autocrine Feedback Can Drive GnRH Secretion: A Modeling Investigation

Pulsatile secretion of GnRH from hypothalamic GnRH neurons tightly regulates the release of mammalian reproductive hormones. Although key factors such as electrical activity and stimulation by kisspeptin have been extensively studied, the underlying mechanisms that regulate GnRH release are still not fully understood. Previously developed mathematical models studied hormonal release and electrical properties of GnRH neurons separately, but they never integrated both components. Herein, we present a more complete biophysical model to investigate how electrical activity and hormonal release interact. The model consists of two components: an electrical submodel comprised of a modified Izhikevich formalism incorporating several key ionic currents to reproduce GnRH neuronal bursting behavior, and a hormonal submodel that incorporates pulsatile kisspeptin stimulation and a GnRH autocrine feedback mechanism. Using the model, we examine the electrical activity of GnRH neurons and how kisspeptin affects GnRH pulsatility. The model reproduces the noise-driven bursting behavior of GnRH neurons as well as the experimentally observed electrophysiological effects induced by GnRH and kisspeptin. Specifically, the model reveals that external application of GnRH causes a transient hyperpolarization followed by an increase in firing frequency, whereas administration of kisspeptin leads to long-lasting depolarization of the neuron. The model also shows that GnRH release follows a pulsatile profile similar to that observed experimentally and that kisspeptin and GnRH exhibit ∼7-1 locking in their pulsatility. These results suggest that external kisspeptin stimulation with a period of ∼8 minutes drives the autocrine mechanism beyond a threshold to generate pronounced GnRH pulses every hour.