Grant Award Funds Epilepsy Research

10/31/2007

Temporal lobe epilepsy (TLE) is among the most prevalent and least medically responsive forms of epilepsy. It is frequently associated with a head trauma, CNS infection, or other brain injury that eventually leads to recurring, spontaneous seizures. A better understanding of seizure-initiating mechanisms may facilitate development of enhanced therapeutic strategies to improve treatment, and might eventually contribute to the development of a cure for epilepsy.

Current therapies for acquired seizure disorders such as TLE are either drastic (removing part of the brain) or purely symptomatic (using drugs to control seizures). No current therapy targets the disease process.

To address this therapeutic need, the National Institute of Neurological Disorders and Stroke awarded Children's Hospital a $6.6 million, five-year program project grant to study the mechanisms underlying the process in which a normal brain becomes epileptic, a process known as epileptogenesis. Douglas A. Coulter, Ph.D., Division of Neurology, leads the study and hopes to identify these mechanisms, target them in patients at risk to develop epilepsy, and develop a way to cure the disorder before the onset of spontaneous seizures.

Investigators led by Dr. Coulter are focusing on GABA, a neurotransmitter that acts at inhibitory synapses in the brain. GABA recycling is required to reload synaptic vesicles following release and is critical to regulating circuit excitability in active areas of the brain. Dr. Coulter's previous investigations have found evidence that GABA recycling mechanisms are compromised in inhibitory synapses in the brains of animals with TLE, and that this alteration develops very soon after the injury that later leads to TLE.

"Compromise in GABA recycling mechanisms appears to be a pivotal, early event in epileptogenesis," says Dr. Coulter. "Restoration of normal GABA production soon after an epileptogenic injury may be a viable therapeutic intervention, capable of blunting the severity of, or completely blocking, the subsequent development of epilepsy."

Using a combination of electrophysiological, molecular and disease model approaches, Dr. Coulter's research will examine the mechanisms mediating GABA production and recycling, and determine the timing of altered GABA recycling during epileptogenesis. In addition, it will determine the consequences of alternate GABA-recycling mechanisms to restore normal function and determine strategies to restore normal recycling or alternate GABA production.

Understanding how changes in metabolic processes within inhibitory synapses influence seizure generation in TLE may lead to early interventions in these processes and alter disease progression, ultimately resulting in new therapeutic strategies to better treat and perhaps cure this devastating disorder.