RATIONALE: This is an application for funding of a study on the role of extrasynaptic alpha5-containing GABA-A receptors in the CA1 and CA3 subfields and in dentate gyrus and inhibitory hippocampal networks for the amnestic action of the general anesthetic etomidate, using a combination of genetic, behavioral and electrophysiological methods. In his previous position at the University of Zurich, by the generation and analysis of mice carrying a point mutation in the alpha5 subunit of the GABA-A receptor, which leads to a partial knockout of this subunit, the applicant's group demonstrated that GABA-A receptors containing the alpha5 subunit modulate defined memory functions. Using novel animal models that have recently been developed in the applicant's laboratory, we propose to characterize the physiological and pharmacological functions of the alpha5 subunit in CA1 and CA3 pyramidal cells and dentate gyrus granule cells of the hippocampus, respectively, using a combination of genetic, electrophysiological, pharmacological, and behavioral techniques, with the major focus on the mechanism of the amnestic actions of general anesthetics.
Intraoperative awareness during general anesthesia has been suggested to occur with an incidence of 0.13% translating to approximately 26,000 cases per year in the United States. The proposal is directed at elucidating the mechanism of action of general anesthetics on learning and memory and the hippocampal inhibitory networks mediating this effect and is expected to lead to novel therapeutic strategies for the development of amnestic drugs to be used in general anesthesia, for the treatment of posttraumatic stress disorder, and potentially also for the development of memory-enhancing drugs e.g. for the treatment of Alzheimer's disease.
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