Meeting Abstract
It has been known for decades that estrogens acutely potentiate neuronal excitability and synaptic transmission in the hippocampus, a brain region involved in learning and memory, affective behavior, and in epilepsy. By what cellular mechanisms do these effects occur and what is their physiological significance? First, I will briefly review in vitro electrophysiological studies showing that estrogens act through membrane-associated receptors to initiate intracellular signaling that regulates synaptic function on a time scale of minutes. Then, I will present evidence that estrogens are produced as neurosteroids in the hippocampus of rats and that neurosteroid estrogens play a role in seizures related to epilepsy. We have used in vivo microdialysis to show that estrogens are synthesized in the hippocampus during limbic seizures and that that seizure severity is related to levels of hippocampal estrogens. Consistent with the seizure-promoting effect of estrogens that is predicted by their acute synaptic effects, blocking estrogen synthesis in the hippocampus strongly suppresses seizures. Behavioral and EEG studies indicate that this occurs through dampening seizure activity in the hippocampus and inhibiting the generalization of seizure activity from limbic to extra-limbic brain regions. Together, these results suggest that acute treatment with an aromatase (estrogen synthase) inhibitor may be a novel anti-seizure treatment. Beyond the implications for epilepsy, these findings raise important questions for future study. For example, how prevalent are extra-nuclear, membrane-associated estrogen receptors in the brain and what proteins do they interact with to alter cellular function? How is neuronal activity coupled to estrogen synthesis in the brain, and does this differ across species? What other normal and pathological brain functions are regulated by neurosteroid estrogens?
