Grant Award Focuses on Genes That May Regulate Receptor Involved in Epilepsy

03/31/2006

Epilepsy affects more than 2.5 million Americans, with up to 20 percent of affected patients suffering severe seizures that are resistant to treatment and can be associated with a shortened life span, social and intellectual impairment, underemployment and a reduced quality of life.

Growing evidence suggests that abnormalities in inhibitory neurotransmission play a critical role in epilepsy. The expression of GABA(A) receptors that mediate the action of the neurotransmitter GABA is the focus of a new study by Children's Hospital investigators, who hope to identify how the expression of key genes involved in nerve-cell transmission are regulated after seizures.

Although the GABA(A) receptors, or GABARs, are the most abundant inhibitory neurotransmitter receptors in the forebrain, little is known about how their expression is regulated either in health or disease.

The award from the National Institutes of Health to Amy Brooks-Kayal, M.D., Division of Neurology, and her collaborator Dr. Shelley Russek at Boston University builds upon previous research that demonstrated long-term changes in the expression of certain GABAR subunits after prolonged seizures, or status epilepticus. These changes, Dr. Brooks-Kayal and her team noted, are associated with marked changes in receptor pharmacology and function.

Recent collaborative studies from the Brooks-Kayal and Russek labs have found that development of epilepsy can be prevented in a subset of animals exposed to status epilepticus by increasing the levels of one GABAR subunit, GABRA1, in certain neurons in the hippocampus using viral gene transfer. The hippocampus is the site where seizures originate in temporal lobe epilepsy — the most common and frequently untreatable form of epilepsy in children and adults. These findings suggest that regulation of GABRA1 expression could be an important target for development of new therapies to prevent or treat epilepsy.

Under the new grant, Drs. Brooks-Kayal, Russek and their colleagues are investigating the regulatory mechanisms that may control expression of the GABRA1 subunit gene. They are specifically examining how two signaling pathways regulate GABRA1 after prolonged seizures.

The investigators will also use proteomics techniques to identify the constellation of transcription factors that interact with the GABRA1 promoter in the signaling pathways and determine if the constellation changes after status epilepticus.

"The studies should clarify the mechanisms that control the expression of the GABRA1gene and how this regulation is altered during the formation of epilepsy," said Dr. Brooks-Kayal. "The results of these studies should facilitate the development of new therapies that may prevent or cure epilepsy by identifying potential new therapeutic targets that specifically regulate GABAR subunit gene expression."