In preliminary studies, the investigator has observed that two volatile anesthetics exert agent-specific actions on two physiologically distinct and anatomically segregated GABAA receptors in hippocampal CA1 pyramidal cells; he has provided evidence that these currents, the cell body GABAA/fast and the dendritic GABAA/slow, mediate suppression of bursting activity and paired-pulse depression, respectively, and thus may have different functional roles with respect to seizures and learning respectively. Preliminary results in which the ability of general anesthetics to enhance GABA function is lost under conditions in which the milieu of the intracellular side of the channel is changed have led to the suggestion that this unique effect of anesthetics on the GABA channel is due to an intracellular action. In the present study Dr. Pearce proposes to test the hypothesis that agent-specific effects on the two GABA currents may account for some clinical differences among agents, and to extend the results to the molecular level. In 3 specific aims, he will (1) test the hypothesis that the separate amnestic and convulsant properties of volatile anesthetics and related agents result from their agent-specific actions on these two currents by extending the series to additional agents including two experimental compounds; (2) examine the mechanisms by which anesthetics alter channel kinetic parameters; and (3) identify the intracellular factors necessary for anesthetic-induced alterations and define their roles. Methods include extracellular and whole cell ruptured patch recording in hippocampal slice, and single channel recordings from excised patches from the slice and from HEK293 cells in which GABAA receptors have been expressed.
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