A significant proportion of women with epilepsy experience increased seizure frequency during phases of the menstrual cycle in which estradiol levels are elevated. This is termed catemenial epilepsy. Animal models of epilepsy also demonstrate that estradiol increases seizure susceptibility. Previous work in the adult female rat has shown that estradiol induces new dendritic spines and axospinous synapses on CA1 pyramidal cells in the hippocampus, a key brain structure in the generation and propagation of seizure activity. Furthermore, estradiol-induced dendritic spines and synapses are correlated with increased excitability of hippocampal neurons and decreased hippocampal seizure threshold. This correlation suggests that estradiol-induced seizure susceptibility in women with catamenial epilepsy may be due, at least in part, to hormone-mediated alterations in hippocampal synaptic connectivity. The studies in this proposal will use the adult female rat to test the hypothesis that estradiol facilitates seizure activity through alteration of hippocampal synaptic structure and physiology. The proposed experiments will use light and electron microscopy, electrophysiological recording from hippocampal slices and behavioral seizure testing to better understand how estradiol-induced changes in synaptic connectivity affect hippocampal neuronal excitability and behavioral seizure susceptibility. Three hypotheses will be tested: 1) Estradiol up-regulates a subpopulation of NMDA receptor-specific excitatory synapses; 2) Estradiol up-regulates GABAA receptor-mediated inhibition; 3)Estradiol-induced changes in hippocampal synaptic structure/function are necessary for estradiol-induced seizure facilitation. These studies will further understanding of estradiol's effects on hippocampal synaptic structure and function. In women with catamenial epilepsy, estradiol-induced changes in hippocampal synaptic connectivity could provide a structural mechanism for the increased seizure frequency seen with elevated estradiol during certain phases of the menstrual cycle. As such, this proposal will lend insight into a mechanism of catamenial epilepsy and suggest a novel role for hormone-mediated structural plasticity in control of seizure susceptibility.
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