This project applies genetic dissection of putative molecular targets of inhaled anesthetics to explain the neurophysiologic basis of their actions. It hypothesizes that type A hippocampal gamma-aminobutryic acid receptors (GABAA-R) mediate part of the amnestic effects of inhaled anesthetics. The project studies hippocampal GABAA-Rs because the hippocampus is central to learning and memory and because inhaled anesthetics enhance the response of GABAA-Rs as do anesthetics (e.g., etomidate) known to cause amnesia by such enhancement. Additionally, a novel genetic approach for creating conditional gene knockin mice will be pioneered. Knockin mice with alterations in specific GABAA-R subunit genes will be created, characterized, and tested. These novel mice will be analyzed in this and other projects within the Program Project with tests spanning molecular, cellular, and behavioral levels. Such a multi-level approach allows a determination of the relevance of a specific drug target (receptor) as a mediator of a specific phenotype (e.g., amnesia). Lastly, collaboration with other project leaders will allow creation of additional genetically engineered mouse lines, including mice with mutant glycine or NMDA receptors, or sodium channels. As with the GABAA-mutant mice, these mice will respond normally to their putative transmitters but will resist the effects of inhaled anesthetics.
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