Voltage‐gated calcium channel activity of gonadotropin‐releasing hormone ( GnRH ) neurons is altered by age and by prenatal androgen exposure in female mice
Year: 2026
Type: article
Abstract: 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.
Source: Journal of Neuroendocrinology
DOI: 10.1111/jne.70268
Institutions: University of Michigan, Michigan Medicine
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,550
OpenAlex ID: W7213601242