Scientists develop 1st genetic mouse model of temporal lobe epilepsy

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Researchers at the Health Science Center have developed the first genetic mouse model for non-convulsive temporal lobe seizures, a common form of epilepsy that affects nearly 600,000 Americans.

Robert Brenner, Ph.D., assistant professor of physiology at the Health Science Center, and Glenn Toney, Ph.D., associate professor of physiology, worked with colleagues at the Health Science Center, Stanford University and Baylor College of Medicine on the project, which was reported in December in Nature Neuroscience.

The physiologists are studying “BK channels,” a family of proteins with major functions in the brain, arteries and smooth muscle. Drs. Brenner and Toney are focusing on the BK channel that controls excitability in neurons, and particularly on an on-off switch called “beta4” that regulates the BK channel activity in these nerve cells.

Beta4 acts as a brake on BK channel function in the hippocampus, a region of the brain responsible for learning and memory and enclosed within the temporal lobes.

“To investigate the function of beta4, we generated mice that we genetically engineered to knock out the beta4 gene,” Dr. Brenner said. “The consequence is that the mice have non-convulsive temporal lobe seizures.” In humans with epilepsy, these seizures also are known as complex-partial seizures.

The researchers determined that the mice were having seizures by making electroencephalogram (EEG) recordings of abnormal brain activity coincident with movies of the mouse behavior. “As the seizure electrical activity ensued, they weren’t having motor convulsions, but had a prolonged period of immobility, similar to the blank staring with impairment of awareness seen in complex-partial seizures in patients with temporal lobe epilepsy,” Dr. Brenner said.

Up to now, this type of epileptic seizures in mouse models has been induced through drug treatment. This examines the environmental contribution, but the new model is said to be important because epilepsy involves both genetic and environmental components.

“For designing drugs, of course you want an animal model that reproduces the specific type of disease,” Dr. Brenner said. “What we’ve done is mutate something (loss of beta4 function) that is one of the linchpins in controlling excitability in this part of the brain. We think this will be a nice animal model for designing drugs against non-convulsant temporal lobe epilepsy.”

The finding is huge, said epileptologist and project collaborator Jose E. Cavazos, M.D., Ph.D., assistant professor of medicine at the Health Science Center. “The significance of Dr. Brenner’s research is that he has developed the first mouse model of temporal lobe epilepsy, convulsant or not. Temporal lobe epilepsy is the most common of the intractable (not controlled by medication) epilepsies. The mechanisms underlying the intractability of this form of epilepsy are not well understood. Dr. Brenner’s model provides us a new tool to examine genetic susceptibility to this type of epileptic seizures.”

A $40,000 grant from the Health Science Center’s Executive Research Committee Research Fund supported the collaborative effort. It involved studies by Dr. Brenner, Dr. Toney, and postdoctoral scientist Qing-Hui Chen, Ph.D., to shed light on the electrical properties of the neurons and the beta4/BK channel interaction; by Jeff Noebels, M.D., Ph.D., at Baylor College of Medicine to perform animal studies and take EEG recordings; and by Rick Aldrich, Ph.D., at Stanford, where the knockout mice were genetically engineered. Dr. Brenner recently was awarded a two-year, $100,000 grant by the Epilepsy Foundation for continued studies on the beta4 knockout mice.

Dr. Brenner, whose Ph.D. is from The University of Texas at Austin, came to the Health Science Center three years ago from Stanford, where he was a postdoctoral fellow in Dr. Aldrich’s laboratory.



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