GENETIC DISSECTION OF INHALED ANESTHETIC TARGETS

该项目将对吸入麻醉剂可能的分子靶点的遗传解剖应用于 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)介导了吸入麻醉剂的部分遗忘效应。该项目研究海马体GABAA-R，因为海马体是学习和记忆的中枢，而且吸入麻醉剂增强了GABAA-R的反应，麻醉剂(例如依托咪酯)也是如此，已知的麻醉剂通过这种增强导致健忘症。此外，还将开创一种创造条件性基因敲击小鼠的新的遗传方法。具有特定GABAA-R亚单位基因改变的Knockin小鼠将被创建、表征和测试。这些新型小鼠将在这个项目和该计划项目中的其他项目中进行分析，测试跨越分子、细胞和行为水平。这种多层次的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)的介体的相关性。最后，与其他项目负责人的合作将允许创建更多的基因工程小鼠品系，包括具有突变的甘氨酸或NMDA受体或钠通道的小鼠。与GABAA突变小鼠一样，这些小鼠将对其假定的递质做出正常反应，但将抵抗吸入麻醉剂的影响。

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.