Regional actions of general anesthetics in inhibitory hippocampal networks

描述(由申请人提供)：这是一项研究的资金申请，该研究采用遗传学、行为学和电生理学相结合的方法，研究突触外含有α5的GABA-A受体在CA1和CA3亚区以及齿状回和抑制性海马网中对全身麻醉剂依托咪酯的遗忘作用的作用。在他之前在苏黎世大学的职位上，通过对携带GABA-A受体Alpha5亚单位点突变的小鼠的产生和分析，导致该亚单位的部分敲除，申请人的团队证明了包含Alpha5亚单位的GABA-A受体调节特定的记忆功能。利用申请人实验室最近开发的新的动物模型，我们建议结合遗传学、电生理学、药理学和行为学技术，分别表征海马CA1和CA3锥体细胞和齿状回颗粒细胞中α5亚单位的生理和药理功能，重点研究全身麻醉药的遗忘作用的机制。公共卫生相关性：全麻术中意识的发生率为0.13%，在美国每年约有26,000例。该提案旨在阐明全麻药对学习和记忆的作用机制以及介导这一作用的海马体抑制网络，并有望为开发用于全身麻醉的遗忘药物、用于治疗创伤后应激障碍以及潜在地开发增强记忆的药物，例如治疗阿尔茨海默病，带来新的治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.