GENETIC DISSECTION OF INHALED ANESTHETIC TARGETS

该项目应用吸入麻醉剂推定分子靶点的基因解剖， 解释他们行为的神经生理学基础。它假设A型海马γ-氨基丁酸受体（GABAA-R）介导吸入麻醉剂的部分遗忘作用。该项目研究海马GABAA-R，因为海马是学习和记忆的中心，并且因为吸入麻醉剂和麻醉剂一样增强GABAA-R的反应（例如，依托咪酯），已知通过这种增强引起健忘症。此外，一种新的遗传方法，创造条件基因敲入小鼠将开创。将创建、表征和检测特异性GABAA-R亚基基因改变的敲入小鼠。这些新型小鼠将在该项目和其他项目中进行分析，测试涵盖分子，细胞和行为水平。这样的多水平方法允许确定特定药物靶标（受体）作为特定表型（例如，健忘症）。最后，与其他项目负责人的合作将允许创建其他基因工程小鼠品系，包括具有突变甘氨酸或NMDA受体或钠通道的小鼠。与GABAA突变小鼠一样，这些小鼠对它们假定的递质反应正常，但会抵抗吸入麻醉剂的作用。

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.