Estrogen fluctuation affects epileptic seizures

In more than a third of women with epilepsy, seizures fluctuate across the menstrual cycle, due in part to continually fluctuating effects of estrogen on the neural circuitry in the hippocampus, a region of the brain involved in learning and memory - and in epileptic seizures.

Northwestern University scientist Dr. Catherine S. Woolley, a pioneer in understanding the effects of hormones on the structure and function of neural circuitry, says understanding how estrogen contributes to seizure activity could lead to novel and needed therapeutic targets for anti-epileptic drugs.

On April 30, Dr. Woolley told fellow scientists meeting at Experimental Biology 2007 in Washington, DC, that new and unexpected findings in her laboratory suggest where such therapies might intervene. Dr. Woolley had been selected to present this year's C. J. Herrick Award Lecture, a distinguished award presented as part of the scientific program of the American Association of Anatomists.

A decade ago, Dr. Woolley discovered that estrogen increases the number of excitatory synapses on neurons in the hippocampus. Excitatory synapses activate neurons, sending and receiving neurotransmitters, explaining how estrogen could enhance learning and memory consolidation. Beyond the fact that estrogen played this role, her findings surprised the scientific community for two more reasons. First, based on natural hormone cycles, the synaptic turnover was very rapid, demonstrating remarkable plasticity of the brain. Second, the estrogen-influenced changes were taking place in the hippocampus, outside what were then considered the traditional hormone-sensitive regions of the brain.

Dr. Woolley's research since has focused on these estrogen fluctuations and how they drive synaptic changes. She now has shown that, in addition to their effect on excitatory synapses that turn on neurons, fluctuating levels of estrogen also have an equally dramatic effect on the inhibitory synapses that silence neurons. Using a combination of electrophysiology to measure synaptic function and nanoscale measurements of synaptic structure, her team has shown that estrogen suppresses the release of inhibitory neurotransmitters, and that this occurs by regulating vesicles at inhibitory synapses (vesicles being the membranes that contain neurotransmitters).

And once again, there was an additional, surprising finding, says Dr. Woolley. Estrogen receptors are typically found in the cell nucleus where they regulate the expression of genes, a relatively slow mechanism to change brain function. Her group found that these receptors also are located on vesicles at inhibitory synapses and that estrogen mobilizes these vesicles toward synapses. The synaptic location of estrogen receptors shows that the effects of this hormone in the brain can be targeted to individual synapses, fine-tuning how neurons communicate, and on a much more rapid time scale then previously appreciated. The estrogen regulation of neurotransmitter vesicles points to novel targets for anti-epilepsy therapies.