Abstracts

Rationale: Both women and men with temporal lobe epilepsy (TLE) are at greater risk for reproductive endocrine disorders, but the neural mechanisms underlying these comorbidities have not been elucidated. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons, the neural output for controlling reproduction, likely play key roles in driving these comorbidities. We recently demonstrated robust estrous cycle disruption in female mice in the intrahippocampal kainic acid (KA) model of TLE. Here we investigated changes in GnRH neuron function in this model of TLE. Methods: Adult GnRH-Cre:Ai9 mice (expressing tdTomato in GnRH neurons) were injected with KA (50 nl of 20 mM) or control saline in the right dorsal hippocampus. 2 mo after injection, targeted extracellular recordings and current-clamp recordings of GnRH neurons were performed in acute coronal brain slices. Trunk blood collected at the time of brain slice preparation was assayed for estradiol and progesterone by ELISA. Hippocampal sclerosis and gliosis in KA-injected mice were verified by Cresyl violet and GFAP staining.  Results: On diestrus, GnRH neuron firing rate was increased in KA-injected female mice that developed prolonged (>7 d) estrous cycles (KA-long n=17 cells vs. saline n=16 cells; p=0.015), but not in KA-injected female mice that maintained regular 4-6 d cycles (KA-regular n=20 cells). Firing rate and cycle length on diestrus were positively correlated (p=0.033). On estrus, GnRH neurons from KA-injected female mice had lower firing rates than controls; this change did not correlate with estrous cycle period (KA-long vs. saline p=0.01, KA-regular vs. saline p=0.01). By contrast, intrinsic excitability, burst duration, and number of spikes per burst were persistently elevated in all KA-injected mice on diestrus and estrus (p<0.001 all parameters, n=5-12 cells/group). Neurons in the medial septum and preoptic area, but not the anterior hypothalamic area, were primarily affected. GnRH neurons also showed a sex-specific response to epilepsy; only cells in the medial septum from KA-injected males showed increased firing. Granule cell dispersion and gliosis confirmed hippocampal scleroses in KA-injected female mice with regular cycles and KA-injected male mice. In KA-injected females, estradiol was higher on estrus regardless of estrous cycle period (KA-long vs. saline p=0.036, KA-regular vs. saline p=0.016). Progesterone was lower in KA-long females on both diestrus (KA-long vs. saline p=0.047, KA-long vs. KA-regular p=0.02) and estrus (KA-long vs. saline p=0.036, KA-long vs. KA-regular p<0.01) (n=7-23 mice/group). Conclusions: Changes in GnRH neuron firing rate demonstrate ovarian-cycle-linked and sex-specific effects in the intrahippocampal KA mouse model of TLE. A subset of KA-injected females maintain regular estrous cyclicity even in the presence of hippocampal sclerosis, demonstrating the utility of this TLE model in recapitulating clinical diversity in development of reproductive co-morbidities. Together, these results provide novel evidence for direct effects of epilepsy on the neural control of reproduction, and indicate that these effects are dynamic across reproductive physiological states. Funding: R01 NS105825 (CAC) and Beckman Institute (JL)