"Potassium channels provide the molecular 'brakes' that help slow down and stop a brain cell when it begins to fire. This newest gene discovery adds to a list of others we have found in a race to discover the causes and cures for people who have epilepsy. When we look at them all, it is beginning to look like 'brake failure' is the most common explanation " said Dr. Jeffrey Noebels, one of the paper's authors and a professor of neurology, neuroscience, and molecular and human genetics at BCM as well as director of the Blue Bird Circle Developmental Neurogenetics Laboratory. Noebels and colleagues in his laboratory have been studying the effects of various ion channels on the brain and in seizure disorders.
In this report, researchers from The Scripps Research Institute in La Jolla, California, BCM, the Novartis Research Foundation in San Diego and Pennsylvania State University in University Park, Pennsylvania, studied what happened when a potassium channel gene called Kv12.2 was completely eliminated or "knocked-out" in specific neurons of the hippocampus, a part of the brain involved in memory. This reduced the threshold for firing (activating) nerve cells in the hippocampus called the hippocampal pyramidal neurons.
Effect on neurons
As a result, these neurons were hyperexcited and fired frequently. The mice experienced spontaneous seizures and were more susceptible to chemicals known to produce seizures. This proved true when the mice lacked the gene for the potassium channel or when its activity was blocked by drugs.
The scientists led by Dr. Timothy Jegla, then with the Salk Institute and now at Penn State, reasoned that because Kv12.2 activity was greater in these neurons, it was likely to contribute to the control of nerve firing.
Relevance to epilepsy
The finding could provide important information about the mechanisms that result in the hyperactive neurons found in epilepsy, as well as better drugs to control the disorder. Over one third of individuals with epilepsy still lack an effective medicine to control their seizures.
Others who took part in this work include: Jong W. Yoo of BCM; Xiaofei Zhang, Federica Bertaso, Karsten Baumgärtel and Sinead M Clancy of Scripps; Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia and Christian Schmed of Novartis.
Funding for this work came from the Genomics Institute of the Novartis Research Foundation, the national Institute of Neurological Disorders and Stroke, the American Heart Association and INSERM.
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