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(Boston)— Researchers at Boston University School of Medicine (BUSM) and The Children’s Hospital of Philadelphia/University of Pennsylvania School of Medicine, have for the first time inhibited the development of epilepsy after a brain injury in animals using a virus that over-expresses a component of a neurotransmitter receptor in neurons. These findings, published as an accelerated communication in the Journal of Neuroscience on November 1, 2006, suggest that using gene therapy to alter signaling pathways in the brain may be a potential opportunity for preventing epilepsy.
Epidemiological evidence suggests that temporal lobe epilepsy (TLE) affects 400,000 Americans. Patients with TLE exhibit a diverse neurological impairment that includes both altered brain physiology and psychopathology. While the onset of TLE in some children and adults can be traced back to an initial brain injury or systemic infection, multiple cases are without such association.
Current medical and surgical interventions are not adequate for all patients with TLE. It is estimated that while many control seizures with antiepileptic drugs, approximately 25 to 30 percent continue to experience recurrent seizures that severely impact the quality of their life, damaging structures of the brain that are necessary for short-term memory, as well as the conscious memory of all facts and events.
Working in a portion of the brain called the dentate gyrus, the researchers focused on one type of cell receptor (type A) for the neurotransmitter gamma-aminobutyric acid (GABA). When GABA(A) receptors are activated, they inhibit the repetitive, excessive firing of brain cells that characterizes a seizure. Seizures are thought to occur, at least in part, because of an imbalance between two types of neurotransmitters: the glutamate system, which stimulates neurons to fire, and the GABA system, which inhibits that brain activity. GABA’s inhibitory role is considered particularly important in the dentate gyrus because the dentate gyrus acts as a gateway for brain activity into the hippocampus, an area that is critical to generating seizures in temporal lobe epilepsy, the most common type of epilepsy in children and adults.
Previous animal research by this group had found that rats with epilepsy had lower levels of the alpha1 subunits of these receptors and higher levels of alpha4 subunits. Therefore, the researchers used gene delivery to alter the expression of the alpha1 subunit to see if this would have an effect on later seizure development.
Rats that had received the gene therapy had elevated levels of alpha1 proteins and either did not develop spontaneous seizures, or took three times as long to experience a spontaneous seizure, compared to rats that did not receive the delivered gene. “We used to think that GABA-A receptors would be the perfect target for gene therapy but they were out of reach because multiple kinds of proteins form the receptor. We now know that we do not have to deliver multiple proteins. We just need to know which protein is the important one,” said Shelley J. Russek, PhD, a molecular neurobiologist in the Pharmacology Department at BUSM.
Collaborators and senior authors Russek and Dr. Amy Brooks-Kayal, a pediatric neurologist/researcher in the Neurology Department at Children’s Hospital of Philadelphia, University of Pennsylvania, have been sharing their expertise to test the hypothesis that altered GABA receptor subunit expression contributes to the development of spontaneous seizures after brain injury.
The National Institutes of Health and the American Epilepsy Society provided grant support that funded this study.