Mechanisms of Seizure in Pregnancy and Preeclampsia

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PROJECT SUMMARY: Eclampsia, diagnosed in women (pregnant and early postpartum) who experience new onset seizures, can be deadly to both the mother and fetus. While a large proportion of eclampsia cases affect women with a diagnosis of preeclampsia, a hypertensive disorder of pregnancy, some women with otherwise healthy pregnancies develop eclampsia. The mechanisms contributing to seizures during pregnancy are not fully known. Currently, magnesium sulfate (MgSO4) is administered to preeclampsia patients with severe symptoms and is effective in preventing seizures when started early. However, the mechanisms by which MgSO4 protects against seizure activity is not fully known and it is still difficult to predict which women will develop seizures. Our preliminary data show that in a rat model of preeclampsia, induced by surgical reduction of utero-placental perfusion pressure (RUPP), seizure sensitivity is increased. We also show that RUPP mice have higher seizure duration and have decreased acid sensing ion channels (ASIC2a) expression in the hippocampus when compared to pregnant mice that underwent sham surgery. ASICs are important for maintaining homeostatic pH especially after increased neuronal activity as occurs in seizures. Genetic knockdown of ASIC2a led to increased seizure severity and longevity in pregnant mice indicating that ASIC2a is important for seizure termination. In this application, we propose to test the hypothesis that MgSO4 acts by reducing inflammation (IL-17 levels) which allows ASICs to function normally to restore homeostatic tissue pH. We will focus on the role of ASIC2a in mediating increased seizure activity in our mouse RUPP model of preeclampsia. We will utilize mice with genetic knockdown of ASIC2a and IL-17ra (the IL-17 receptor) and induce seizures pharmacologically using pentylenetetrazol. We will use acute administration of MgSO4 to assess the mechanisms of action in preventing or reducing seizure activity in mice subjected to sham or RUPP surgery. We propose to answer the following questions: 1) Does knockdown of ASIC2a exacerbate RUPP-induced increases in seizure sensitivity? 2) Is ASIC2a required for MgSO4 to have anti-seizure effects in our mouse model of preeclampsia? 3) Is increased IL-17 responsible for RUPP-induced increases in seizure sensitivity and does IL-17 regulate ASIC2a expression? By answering these questions, we will identify new therapeutic targets for eclampsia and will have a better understanding of the mechanisms of action of MgSO4 which represents major advances in the field of neurology and obstetrics.