The training and research program described in this proposal supports the application for a Clinical Investigator Development Award for Dr. Kevin Staley. The proposed program will enable Dr. Staley to develop, under the supervision of Dr. David Prince, the skills necessary to pursue a research career in the area of pediatric epilepsy. The proposed research is motivated by the clinical difficulties involved in the treatment of neonatal seizures. The goal of this project is to evaluate two of the many possible hypotheses regarding the poor response of neonatal seizures to current anticonvulsant therapy. These hypotheses are based on the well-documented immaturity of the hippocampal GABAergic inhibitory system in the neonatal rat hippocampus, and the conditions under which GABAA receptor-mediated functions have been shown to be decreased. 1) Is modulation of GABAA inhibition by barbiturates and benzodiazepines different in the neonatal vs adult hippocampus? 2) Are the effects of the barbiturates and benzodiazepines on the GABAA system minimized under conditions which are likely to occur during neonatal seizures: depletion of presynaptic GABA, alteration in transmembrane ionic gradients, accumulation of intracellular free calcium, and the depletion of intracellular high-energy phosphates? The research will focus on the modulation of GABAA receptor-mediated inhibition in areas CA1 and CA3 of the in vitro hippocampal slice preparation, and will utilize the whole-cell patch clamp recording technique. Experiments include 1) Measurement of the effects of barbiturates and benzodiazepines on GABAA receptor-mediated evoked and spontaneous synaptic events; 2) Determination of the effects of barbiturates and benzodiazepines on GABAA synaptic events under conditions which are likely to occur during neonatal seizures 3) Assessment of alternative modulators of GABAergic inhibition such as GABA- aminotransferase inhibitors and steroids.
| Staley, K J; Soldo, B L; Proctor, W R (1995) Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 269:977-81 |
| Staley, K (1992) Enhancement of the excitatory actions of GABA by barbiturates and benzodiazepines. Neurosci Lett 146:105-7 |
| Holley, J A; Silver, J (1987) Growth pattern of pioneering chick spinal cord axons. Dev Biol 123:375-88 |
