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Epilepsy-induced brain cell damage prevented in the laboratory

October 30, 2007

For some epilepsy patients, the side effects of epilepsy can be as troubling as the seizures. One pressing concern is the cognitive impairment seizures often inflict, which potentially includes memory loss, slowed reactions and reduced attention spans.

Now scientists at Washington University School of Medicine in St. Louis have directly observed seizure-induced structural changes in brain cells in laboratory animals. They report in The Journal of Neuroscience that the insights they gained allowed them to use a drug to block those changes in the brain.

"Assuming that these structural changes are linked to cognitive impairment -- and there's a lot of data to suggest that's true - then this could provide us with a path to therapies that reduce cognitive problems in epilepsy," says senior author Michael Wong, M.D., Ph.D., assistant professor of neurology, of anatomy and neurobiology, and of pediatrics.

Approximately 1 to 2 percent of the general population suffers from some form of epilepsy. Severe or prolonged seizures can cause brain cell death, leading to anatomic damage visible on brain scans. But in some cases the cognitive impairments caused by seizures cannot be linked to discernible brain damage.

Prior studies have suggested that seizures may damage dendrites, treelike branches that extend from a nerve cell to receive signals. In studies of human tissue, researchers noted the loss of spines, small bumps on the exterior of the dendrite. Spines are known to be important for the formation of synapses, junctions where two nerve cells communicate across a small gap.

"Previous studies were helpful in suggesting that dendrite structure was being damaged, but they couldn't prove cause-and-effect and provided only limited information on the timing and mechanisms of the processes that led to damage," says Wong.

Led by postdoctoral fellows Ling-hui Zeng, M.D., Ph.D. and Lin Xu, Ph.D., a team of researcher's in Wong's laboratory applied an approach known as multiphoton imaging to track brain cell changes during seizures. They used a drug to induce seizures in mice and imaged brain cells before, during and after seizures.

"Within minutes, we found changes were happening quite rapidly in the dendrites," Wong says. "They would become swollen and the spines would disappear. After the seizure, the swelling would go down but the spines did not return. That continued to be the case for at least 24 hours."

Scientists think spines may be linked to long-term potentiation, a phenomenon that makes it easier for messages to pass between nerve cells and may be essential for the encoding of memories. This could mean loss of spines in seizures impairs learning.

When researchers probed the mechanisms behind the spine loss, they found seizures were causing the breakdown of actin, a molecule widely used in cell structures. When they gave the mice a drug, FK506, prior to inducing seizures, they were able to block that breakdown.

"To follow-up, we're going to be looking at whether we can tie these changes in dendrite structure to behavioral changes in the mice," Woo says. "We're also going to be searching for drugs that can reverse this effect after a seizure happens. We would like to avoid putting epilepsy patients on a new drug all the time and hope instead to find something that can be given immediately after a seizure to prevent cognitive impairment."



Washington University School of Medicine