Sex-Dependent Changes in Gonadotropin-Releasing Hormone Neuron Voltage-Gated Potassium Currents in a Mouse Model of Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and people with TLE exhibit higher rates of reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate reproductive function in mammals by regulating gonadotropin secretion from the anterior pituitary. Previous research demonstrated GnRH neuron hyperexcitability in both sexes in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Fast-inactivating A-type (I_A) and delayed rectifier K-type (I_K) K⁺ currents play critical roles in modulating neuronal excitability, including in GnRH neurons. Here, we tested the hypothesis that GnRH neuron hyper-excitability is associated with reduced I_A and I_K conductances. At 2 months after IHKA or control saline injection, when IHKA mice exhibit chronic epilepsy, we recorded GnRH neuron excitability, I_A, and I_K using whole-cell patch-clamp electrophysiology. GnRH neurons from both IHKA male and diestrus female GnRH-GFP mice exhibited hyperexcitability compared with controls. In IHKA males, although maximum I_A current density was increased, I_K recovery from inactivation was significantly slower, consistent with a hyperexcitability phenotype. In IHKA females, however, both I_A and I_K were unchanged. Sex differences were not observed in I_A or I_K properties in controls, but IHKA mice exhibited sex effects in I_A properties. These results indicate that although the emergent phenotype of increased GnRH neuron excitability is similar in IHKA males and diestrus females, the underlying mechanisms are distinct. This study thus highlights sex-specific changes in voltage-gated K⁺ currents in GnRH neurons in a mouse model of TLE and suggesting potential sex differences in GnRH neuron ion channel properties.