Researchers Pinpoint Site For Petit Mal Seizures In Brain

April 29, 1996

BALTIMORE, Md. -- Using a type of mouse genetically prone to petit mal seizures, researchers at Duke University Medical Center reported Monday finding new clues about the precise location in the brain that causes the common childhood form of epilepsy.

The findings may lead to more specific drugs for the disorder with fewer side effects, said Dr. David Hosford, assistant professor of neurology at Duke and the Durham Veterans Affairs Medical Center.

Petit mal or "absence" seizures affect 100,000 children in the United States and account for one-fifth of all childhood epilepsies. About 20 percent of children with petit mal seizures aren't helped by currently used drugs and another 20 percent experience side effects, such as inability to concentrate.

The findings were prepared for presentation by Sarah Caddick, a post-doctoral fellow in neurology at Duke and the Durham V.A. Medical Center, at the American Epilepsy Society's annual meeting. The work was supported by the National Institute of Neurologic Diseases and Stroke and a V.A. merit award.

Children affected by petit mal seizures have up to hundreds of seconds-long lapses of consciousness, during which they stare blankly and may blink rapidly or sway before recovering.

"Absence seizures usually take hold at a critical period in a child's initial education, and may be interpreted as a learning disability or isolate them from other children," Caddick said in an interview at Duke. "If these studies lead to more effective treatments, they can have a more profound effect on a child's development than merely preventing the seizure."

Previously, the Duke researchers had reported that mice with petit mal seizures have an overabundance of a protein called a GABAb receptor in the brain. These receptor proteins are found in cells throughout the body, and respond to a neurotransmitter signal called gamma aminobutyric acid, or GABA, which is one of a dozen or so known neurotransmitter molecules. GABAb receptors are thought to act as a brake on nerve cell activity, Hosford said. But their exact function in the brain is unknown.

Using a mouse prone to petit mal seizures, the researchers have localized the petit mal defect -- the overabundence of GABAb receptors -- to specific neurons in the thalamus, a nerve relay center in the brain. During waking hours, the thalamus continually funnels messages from all parts of the nervous system to the neocortex, the portion of the brain that processes higher functions such as language.

"In a sense the thalamus is thought to be the gateway to consciousness," Hosford said. "During a petit mal seizure, the thalamus switches to a burst pattern of signal transmission, similar to what we see in sleep. In a sense, the petit mal seizure is like a momentary lapse into sleep."

To determine where in the neural signaling process the defect lies, Caddick measured the function of GABAb receptors at the junction between nerve cells where signals are transmitted from one nerve to the next. She showed that GABAb receptors that receive signals are normal in the mouse thalamus, suggesting the defect lies on the sending side of neural transmission.

"Most people think of receptors as being important in receiving signals, but this result suggests we should be looking at the sending side of the neuron," Hosford said.

Hosford has already shown that drugs that inhibit GABAb receptors control seizures in the mice genetically prone to petit mal epilepsy. The new information will allow the research team to pinpoint the exact mechanism by which GABAb receptors can cause absence seizures. Armed with the new information about the mechanism, Hosford plans to look for compounds that inhibit only those GABAb receptors affected in petit mal seizures, which the scientists hope will allow them to develop a treatment that works as well as current drugs, but with fewer side effects.
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Duke University

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