∂Voltage-gated calcium channel activity of gonadotropin-releasing hormone (GnRH) neurons is altered by age and by prenatal androgen exposure in female mice.

UNLABELLED: Polycystic ovary syndrome (PCOS), a common cause of infertility, is marked by persistently high luteinizing hormone (LH)-pulse frequency, presumably driven by high-frequency GnRH pulses. Prenatally androgenized (PNA) mice mimic neuroendocrine PCOS symptoms including high LH-pulse frequency. GnRH neurons from adult PNA mice have a higher firing rate than those from vehicle (VEH) mice; this is reversed in prepubertal mice despite more excitatory inputs at both ages. We hypothesized voltage-gated Ca 2+ currents (I Ca ) help set intrinsic excitability of GnRH neurons and are altered by development and/or PNA treatment. Whole-cell patch-clamp recordings were used to measure GnRH neuron I Ca in 3wk-old and adult VEH and PNA mice. PNA treatment increased I Ca density and depolarized the I Ca -half inactivation potential at both ages. In VEH but not PNA mice, the Ca 2+ -half activation potential was depolarized in adults versus 3wks. Age decreased the inactivation rate of a fast I Ca regardless of PNA treatment. GnRH neuron firing rate during current injections was higher at 3wks than in adulthood in VEH mice only. Blocking small-conductance Ca²⁺-activated K⁺ current with apamin increased GnRH neuron firing rate except in adult PNA mice. Apamin changed the post-spike-train membrane response from hyperpolarization to depolarization; during development, this net effect of apamin became smaller in PNA mice. In summary, while GnRH neurons from PNA mice have increased I Ca , they lack some developmental changes in I Ca kinetics and intrinsic excitability observed in VEH mice. Ca²⁺-activated K⁺ currents are less prominent in GnRH neurons from adult PNA mice, perhaps contributing to increased spontaneous firing.

SIGNIFICANCE STATEMENT: Hyperactivation of GnRH neurons, which control reproductive endocrine function, can lead to increased LH-pulse frequency and is a hallmark of hyperandrogenemia polycystic ovary syndrome (PCOS). We used a mouse model of prenatal androgenization (PNA) that recapitulates the neuroendocrine aspects of PCOS to test the role of calcium currents (I Ca ) in the PNA phenotype and the typical pubertal process. PNA treatment increased I Ca in GnRH neurons both before and after puberty. Calcium plays a crucial role in neurosecretion thus this may enhance GnRH release. Another role of calcium is activation of calcium-sensitive potassium currents, which tend to decrease action potential firing rate. Despite increased I Ca, calcium-activated potassium currents are less effective in adult PNA mice, perhaps contributing to GnRH neuron hyperactivation.