GnRH neuron excitability and action potential properties change with development but are not affected by prenatal androgen exposure.

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current clamp recordings were made from GnRH neurons in brain slices from control and PNA females before puberty at 3-wks of age and in adulthood to measure GnRH neuron excitability and action potential properties. GnRH neurons from adult females were more excitable and required less current to initiate action potential firing compared to 3-wk old females. Further, the afterhyperpolarization potential of the first spike was larger and its peak was delayed in adulthood. These results indicate development, not PNA, is a primary driver of changes to GnRH neuron intrinsic properties and suggest there may be developmentally-induced changes to voltage-gated ion channels in GnRH neurons that alter how these cells respond to synaptic input. Significance Statement Gonadotropin-releasing hormone (GnRH) neurons play a crucial role in reproductive function. Disruptions to the release of pattern of GnRH secretion are implicated in fertility disorders, such as polycystic ovary syndrome (PCOS). Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in women diagnosed with PCOS. We used electrophysiology to study how the intrinsic properties of GnRH neurons are altered with pubertal development and with PNA treatment. We found that pre vs post pubertal GnRH neurons had different properties, including increased excitability after puberty. PNA treatment did not affect these typical developmental changes. These data suggest the postulate that development, rather than androgen exposure, is a primary regulator of the voltage-gated ion channels of GnRH neurons.