GABA-A Receptor Function in Pediatric Focal Cortical Dysplasia

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DESCRIPTION (provided by applicant): The applicant is a physician-scientist trained in clinical pediatric neurology and experimental neurophysiology and neuropharmacology. Receipt of the Mentored Clinical Scientist Development Award would allow the candidate to consolidate her previous training in order to become an independent investigator in the field of pediatric epilepsy research. Despite advances in the pharmacologic and surgical treatment of epilepsy, intractable seizures remain a substantial cause of morbidity and loss of potential in children. Epileptogenic areas of focal cortical dysplasia (FCD) are a common source of intractable seizures, yet the physiology and, therefore, the optimal management of these regions is poorly understood. This proposal endeavors to address the hypothesis that abnormal GABA-A receptor function is present in FCD, and is a factor in the pathogenesis of epilepsy and poor response to antiepileptic drug treatment. This hypothesis will be tested through the use of a recently described technique allowing electrophysiologic analysis of human GABA-A receptors in their native configuration after injection of Xenopus oocytes with cellular membranes isolated from brain specimens. The Specific Aims of this proposal include: 1) Establishment of methods for measurement of GABA-A receptor currents from pediatric control and FCD surgical specimens after membrane injection into Xenopus oocytes, 2) analysis of intrinsic physiologic properties of GABA-A receptors in control and FCD specimens, 3) comparison of the responses of GABA-A receptor currents to pharmacologic agents, including antiepileptic drugs and endogenous modulators, in control and FCD specimens, and 4) correlation of electrophysiologic findings with clinical course and response to antiepileptic drugs. The results of this study will provide additional insight into the role of GABA-A receptors in epilepsy and assist in optimization of the treatment of intractable seizures due to FCD. The candidate has recently assumed a position with the Department of Neurology at the University of Washington and Children's Hospital and Regional Medical Center, which is committed to her development as an independent investigator through the provision of ample protected time, research facilities, and instruction. Bruce R. Ransom, MD PhD, who has exceptional experience in the study of central nervous system cellular physiology as well as in the supervision of physician scientists, will serve as the applicant's mentor in the development of her academic career. An Advisory Committee consisting of established investigators within the Department of Neurology will also be assembled to provide additional guidance.