The study, conducted in baby rats, appears in the March issue of Nature Medicine and is the first to link the structure, called an "h-channel," to any neurological disease.  The research suggests that studies on h-channels in the brain eventually could be used to develop new classes of drugs to treat childhood seizures and perhaps even to prevent epilepsy.  Febrile (fever-induced) seizures are the most common type of seizure in childhood, affecting up to 5 percent of children worldwide.

Ivan Soltesz, associate professor of anatomy and neurobiology, Dr. Tallie Z. Baram, the Danette D. Shepard Chair in Neurological Sciences, and colleagues found that h-channels' behavior changed in the brains of rats which experienced long fever-induced seizures.  The altered h-channels further stimulated nerve cells to fire even faster, creating more seizures.  The finding helps explain why previous research had shown that later seizures were more likely to occur after the first episode of prolonged febrile seizures, despite an apparently increased inhibition of nerve cells that--theoretically--should have prevented seizures.

In the healthy, seizure-free brain, the firing of nerve cells occurs in a delicate balance between excitation and inhibition.  Until recently, excessive firing has been thought to occur as a result of either too much excitation or too little inhibition.  However, the researchers' previous studies showed that rats that had prolonged febrile seizures 10 days after birth had more inhibition in their nerve cells.  Despite this inhibition, the rats tended to develop seizures later in life.

"The excitatory and inhibitory control of nerve-cell firing can be thought of as the accelerating and braking systems of cars," Soltesz said.  "In the seizure-free brain, h-channels play a role of gently opposing the braking system, making sure that the slowing down of the car occurs in a manner that does not cause the car to spin out of control.  However, in the brains of rats that had prolonged febrile seizures early in life, the h-channels become hypersensitive and too strong.  As a result, even though there is more inhibition (akin to stepping on the brake harder), the altered h-channels limit the effectiveness of inhibition and can cause over-excitation, leading to seizures."

H-channels are found throughout the brain, where they play an important role in regulating sleep.  They also are found in the heart, where they generate "pacemaker" electrical currents that maintain a regular heartbeat.  While some researchers have focused on the h-channels in the heart as possible targets for drugs to treat heart disease, the UCI study is the first to investigate these channels as potential targets in curing neurological disease.

"In order to develop treatments for seizures targeting h-channels, it will be important to find chemicals that affect the h-channels in the brain without changing the activity of heart h-channels." Soltesz said.  "We need to study in detail the effects of the h-channels on brain cells after seizures and understand the differences between heart and brain h-channels before any effective treatment can be created."

The researchers are now looking at what other factors may change the behavior of h-channels, whether the changes in channel function are associated with changes in their molecular structure, and how long the channels can encourage seizures to occur. 

Soltesz' and Baram's colleagues in the study included Kang Chen, Ildiko Aradi, Niklas Thon and Mariam Eghbal-Ahmadi of UCI.  The research was supported by grants from the National Institutes of Health, the University of California Systemwide Biotechnology Research and Education Program and the Epilepsy Foundation of America.

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Contact:
Andrew Porterfield
(949) 824.3969
amporter@uci.edu

Contact
Andrew Porterfield
(949) 824-3969
amporter@uci.edu