July 19, 2002

Epilepsy research targets brain chatter

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Dr. Robert Macdonald, chairman of Neurology, has a goal to boost the department into the top 10 in the nation.

Epilepsy research targets brain chatter

They’ve topped the list of suspects for years. The crime: causing epilepsy. And recent studies make it all but certain that GABAA receptors — proteins that normally quiet the brain’s excited chatter — are guilty as charged.

“It was logical that malfunctions of the GABAA receptor would cause epilepsy,” said Dr. Robert L. Macdonald, professor and chair of Neurology, who has studied these receptors for more than 25 years. Logical, because GABAA receptors are the major inhibitory receptors in the brain and might therefore dampen the hyperexcitability that characterizes seizures. And logical because some anti-seizure drugs, like phenobarbital, work by enhancing the quieting activity of GABAA receptors.

Though investigators have searched for epilepsy-associated GABAA receptor mutations “forever,” Macdonald said, the first mutations were reported just last year. Macdonald and colleagues have now described the functional consequences of these GABAA receptor mutations. Their findings, reported in the July 1 issue of the Journal of Neuroscience, shed light on the mechanisms underlying epilepsy and pave the way toward targeted therapies for this complex neurological disorder.

More than 2 million Americans have epilepsy, a disorder with multiple causes ranging from abnormal brain development to brain damage from illness or injury to genetic mutations.

Linking specific genes to epilepsy syndromes is one of the more exciting epilepsy research advances, according to Macdonald. Though the percentage of epilepsy syndromes currently known to be inherited is small, he said, that number will undoubtedly grow. “There’s a very large category of idiopathic epilepsies — cause unknown,” Macdonald said, “and my guess is that a very high percentage of those are going to turn out to have genetic causes.”

The genetic mutations studied by Macdonald and colleagues were in the GABAA receptor gamma subunit — one of several protein “parts” that come together to make a functional receptor. GABAA receptors quiet neuronal traffic by changing the electrical activity of neurons. When the chemical GABA binds to the receptors, they let electrical current flow across the cell membrane.

Phenobarbital and other barbiturate drugs and anti-anxiety drugs like Valium exert their calming effects by increasing the current flow through GABAA receptors.

Macdonald’s group is one of only a handful in the world that studies GABAA receptor function using a very sensitive “fast perfusion” technique. The method allows the investigators to characterize GABAA receptors in a way that simulates their native environment — the neuronal synapse — and the very rapid time scales of neuronal activity.

The two mutations characterized by Macdonald’s group cause less current to flow — one by reducing the amplitude of the current, the other by shortening it. If you picture the amount of current as a rectangle, Macdonald said, “one mutation dropped the top, and the other one pulled in the sides.”

“These are the first mechanistic descriptions of GABAA receptor mutations that cause epilepsy,” he added.

Identifying the genes responsible for inherited epilepsies opens the possibility of targeted therapies, Macdonald said. “Families with different gene mutations may require totally different therapies that you can now design for their epilepsies,” he said.

Interestingly, Macdonald noted, the syndromes that are being associated with GABAA receptor mutations are generalized epilepsies — those in which seizures affect the entire brain — not partial or focal epilepsies. The generalized epilepsies have long been considered to have genetic underpinnings, he said.

“This is just the beginning of a huge area of investigation, diagnosis, and treatment of a whole large group of epilepsies that were previously inaccessible,” Macdonald said. “It’s a very exciting time for epilepsy research.”

Graduate student Matt Bianchi and research associates Luyan Song and Helen Zhang contributed to the work. The research was supported by the National Institutes of Health.