A five-year training program providing the applicant with the opportunity to develop the knowledge and skills required to perform future independent investigations in synapse physiology and the basic mechanisms of epilepsy is proposed. Having completed clinical training in child neurology and clinical neurophysiology at Children's Hospital Boston, the principal investigator is now an Assistant Professor of Neurology and Pediatrics at the University of Virginia. The opportunity to expand upon his scientific skills under the mentorship of Dr. Jaideep Kapur, a recognized leader in the basic mechanisms of epilepsy, and the UVA Department of Neurology's commitment to this candidate makes UVA the ideal setting for the applicant's training as a physician-scientist. The proposed research will focus on providing an improved understanding of the changes that occur at inhibitory synapses during status epilepticus. First line therapies for the treatment of status epilepticus, which target inhibitory synaptic transmission, often fail leaving the patient at risk for mortality or significant neurological morbidity. It is posited that an improved understanding of the changes that occur at inhibitory synapses during status epilepticus will provide a framework on which to base new therapies with the goal of improving the prognosis for those who present in status epilepticus. While two distinct lines of evidence suggest that an alteration in inhibitory synaptic transmission does occur during status epilepticus and that this alteration is, in part, the result of a modification in the complement of GABAA receptors present at the synapse, the mechanism underlying the modification is not known. Using an in vitro and an in vivo model of status epilepticus combined with electrophysiological and cellular imaging techniques, the mechanism underlying the modification in the post-synaptic GABAA receptor population will be investigated by completing four Specific Aims: 1) To characterize the impact of in vitro status epilepticus on GABA-mediated synaptic transmission by means of patch clamp recording, 2) To characterize the impact of in vivo status epilepticus on GABA-mediated synaptic transmission by means of patch clamp recording, 3) To characterize the impact of status epilepticus on the rate of internalization and distribution of GABAA receptors by means of immunocytochemistry combined with microscopy and 4) To characterize the impact of status epilepticus on GABA release from the pre-synaptic terminals by means of patch clamp recording.
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