Therapeutic options for women with epilepsy, particularly temporal lobe epilepsy, are complicated by complex interactions between the neural control of ovarian steroid hormone production and feedback effects of these hormones on epileptogenic brain structures. In addition, menstrual and reproductive endocrine disorders are prominent, but understudied, co-morbidities of epilepsy in women. Clinical evidence suggests that these interactions are significantly affected by the side of the brain on which the seizures initiate (i.e., the seizure focus). However, this has not been demonstrated in animal models of temporal lobe epilepsy. Consistent with the goals of the NINDS R03 mechanism, the overall objectives of the proposed studies are to perform a novel phenotypic screen of the progression of changes in hypothalamic-pituitary-ovarian (HPO) axis function, reproductive estrous cyclicity, and seizure incidence in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy. In a recent publication, our laboratory demonstrated that kainic acid injection in the right dorsal hippocampus leads to development of disrupted estrous cycles in the majority of mice within 2 months. Our preliminary data indicate that circulating levels of the sex steroids estradiol and progesterone are also altered in this model. In the proposed work, we will systematically compare the impacts of targeting the kainic acid injection to either the left or right hippocampus.
Aim 1 will assess the time course of changes in estrous cyclicity, ovarian follicular development, and sex steroid hormone levels in female mice treated with kainic acid in left vs. right hippocampus.
In Aim 2, we will use video/EEG recordings to quantify seizure activity across all estrous cycle stages after injection of kainic acid in left vs. right hippocampus, and the time course of development of this interaction. Development of rodent models that recapitulate epilepsy-related menstrual and reproductive endocrine disorders, and associated effects on seizure patterning, will have positive translational impact by providing new tools for necessary mechanistic investigations to address this important problem in women's health.
Women with temporal lobe epilepsy are at increased risk of developing reproductive endocrine disorders, and reciprocally, fluctuations in ovarian hormone levels at different phases of the menstrual cycle can influence seizure incidence. Clinical studies suggest that the side of the brain on which temporal lobe seizures start impacts the type of endocrine disorder that arises, as well as the pattern of seizures across the menstrual cycle. This proposal investigates the impacts of left- vs. right-sided targeting of seizures in female mice, with the goal of developing research models that better mimic these effects in women with epilepsy.
| Li, Jiang; Robare, Jordyn A; Gao, Liying et al. (2018) Dynamic and Sex-Specific Changes in Gonadotropin-Releasing Hormone Neuron Activity and Excitability in a Mouse Model of Temporal Lobe Epilepsy. eNeuro 5: |
