Differential roles of neuronal and astrocytic aromatase in status epilepticus and chronic epilepsy

项目总结

PROJECT SUMMARY A relationship between estrogens and epilepsy has long been acknowledged with estrogens, such as estradiol, primarily linked to proconvulsant effects. The ovaries traditionally receive the most attention as sources of estradiol, particularly in the context of catamenial seizure exacerbations in association with certain estradiol- dominant phases of the menstrual cycle in women. However, the brain itself is a source of estradiol in both sexes. Estradiol is synthesized from testosterone by the aromatase enzyme, which is highly expressed in the brain, particularly in areas strongly implicated in epilepsy. In the hippocampus, aromatase is almost exclusively expressed in neurons in basal conditions, but after trauma such as injury or stroke, astrocytes can also show high levels of aromatase expression. Roles for brain-derived estradiol in epilepsy, and the specific roles of neurons and astrocytes as sources of estradiol in this relationship, remain unclear. The proposed research will address major gaps in knowledge regarding the relative contributions of aromatase and estrogen synthesis in neurons vs. astrocytes in relation to two distinct states of seizure activity: status epilepticus (SE) and chronic epilepsy, the state of spontaneous recurrent seizures. Our rationale is that understanding distinct roles of neurons and astrocytes as sources of estrogens at different phases of SE and epilepsy will enable development of new therapeutic strategies to selectively target production of brain-derived estrogens and maximize seizure- suppressive effects, while minimizing deleterious effects on synaptic function and memory. We will use a novel combination of transgenic mice and controlled cell-specific reduction of aromatase, in combination with 24-hour video-EEG monitoring of seizures, multilabel immunofluorescence microscopy, and biochemical measurement of hippocampal estradiol to test our overall hypothesis that neurons and astrocytes have differential roles as sources of hippocampal estradiol in SE and chronic epilepsy. In Aim 1, we will define the temporal dynamics of hippocampal neuronal and astrocytic aromatase expression in association with SE, epileptogenesis, and chronic epilepsy. In Aims 2 and 3, we will determine the roles of hippocampal neuronal vs. astrocytic aromatase in SE susceptibility and chronic epilepsy, respectively. These studies will use a mouse model of epilepsy that recapitulates several critical EEG and histopathological features of human temporal lobe epilepsy. These studies will have positive translational impact by providing new insights into the dynamics of aromatase expression in neurons and astrocytes in SE and chronic epilepsy, and thereby address multiple goals of the 2020 NINDS Epilepsy Research Benchmarks to understand causes of epilepsy and related neurologic conditions, to prevent the progression of epilepsy, and improve treatment options while minimizing side effects.