Lateralized targeting of hippocampus to model interactions between epilepsy and reproductive endocrine disorders

University Of Illinois At Urbana-Champaign, Urbana IL

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Abstract

PROJECT SUMMARY 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.