The Essential Role of Presynaptic NMDA Receptors in The Fast Antidepressant Actions of Ketamine and Its Metabolite

突触前 NMDA 受体在氯胺酮及其代谢物快速抗抑郁作用中的重要作用

• 批准号: 9526812
• 负责人: Xiang Cai
• 金额: $ 35.1万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9526812
• 关键词: AMPA Receptors; Adverse effects; Adverse reactions; Animal Experiments; Antidepressive Agents; Behavior; Behavioral; Biological; Biotinylation; Cell surface; Cells; Chemosensitization; Clinical Trials; Development; Dialysis procedure; Dose; Down-Regulation; Electrophysiology (science); Evaluation; Event; Exhibits; Exocytosis; Experimental Designs; GABA Receptor; Generations; Glutamate Receptor; Glutamates; HCN1 gene; Hippocampus (Brain); In Vitro; Ketamine; Knock-in Mouse; Knockout Mice; Knowledge; Location; MK801; Measurement; Mediating; Membrane Proteins; Mental Depression; Molecular; N-Methyl-D-Aspartate Receptors; NR1 gene; Neurons; PKA inhibitor; Patients; Phosphorylation; Property; Proteins; Pyramidal Cells; Receptor Inhibition; Reporting; Role; Signal Transduction; Site; Surface; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic; Western Blotting; antidepressant effect; base; behavior measurement; club drug; depressive symptoms; design; experimental study; hippocampal pyramidal neuron; in vivo; multidisciplinary; next generation; patch clamp; postsynaptic; presynaptic; prevent; response; treatment-resistant depression

Project Summary/Abstract Evidence from clinical trials and animal experiments shows a single subanesthesia dose of ketamine produces rapid antidepressant responses. However, the psychotomimetic properties and abuse potential of ketamine necessitate caution in promoting this compound to be used as a general treatment of depression. The reports on the mechanisms underlying the rapid-acting antidepressant effects of ketamine are controversial. Particularly, it remains uncertain which molecular events mediate ketamine’s or its metabolites’ action in enhancing excitatory synaptic transmission. In preliminary experiments, it was observed that both ketamine and its metabolite, cis-6-HNK, potently enhanced Shaffer collateral-CA1 (SC-CA1) EPSCs and fEPSPs. These actions were mimicked and completely occluded by MK-801, but not eliminated by GABA receptor blockade. Ketamine potently increased total and surface GluA1 expression and the phosphorylation of GluA1 Ser845 site. In addition, ketamine failed to potentiate SC-CA1 fEPSPs and induce the antidepressant-like responses in GluA1 S845A knock-in mice. Furthermore, deletion of NMDA receptor on CA3 neurons but not on CA1 cells completely eliminated ketamine-induced potentiation on SC-CA1 synaptic transmission. In the proposed project experiments are designed to test the role of GluA1 Ser845 phosphorylation and presynaptic NMDA receptors in ketamine- and HNK-produced rapid-acting antidepressant responses as well as their celluar and molecular bases. Electrophysiological techniques will be combined, including whole-cell patch clamp with cell biological technique such as Western blotting, biotinylation of surface proteins and GluR1 S845A knock-in mice, CA1 cell- or CA3 cell-specific NR1 knockout mice, HCN1 knockout mice as well as behavioral measurements to achieve the designed experiments. The proposed project will expand knowledge in understanding the cellular mechanisms of fast-acting antidepressant actions of ketamine. A better understanding of ketamine’s fast-acting antidepressant effects will promote the design of a new generation of rapid-acting antidepressant to offer a better therapy to depression.

项目摘要/摘要 来自临床试验和动物实验的证据表明，单个亚麻醉剂量 氯胺酮会产生快速的抗抑郁反应。但是，精神病特性 氯胺酮的滥用潜力需要谨慎促进这种化合物用作 抑郁症的一般治疗。关于快速作用的机制的报告 氯胺酮的抗抑郁作用是有争议的。特别是，仍然不确定哪个 分子事件介导氯胺酮或其代谢物在增强兴奋性突触的作用 传播。在初步实验中，观察到氯胺酮及其代谢产物都 顺式6-HNK，有可能增强的Shaffer Collat​​eral-CA1（SC-CA1）EPSC和FEPSP。这些 动作模仿了MK-801，但没有被GABA淘汰 接收器封锁。氯胺酮可能增加总和表面表达和表面表达 GLUA1 Ser845位点的磷酸化。此外，氯胺酮未能潜在SC-CA1 FEPSP 并诱导GLUA1 S845A敲入小鼠中的抗抑郁样反应。此外， 在CA3神经元上删除NMDA受体，但在CA1细胞上删除完全消除 氯胺酮诱导的SC-CA1突触传递上的增强。在拟议的项目中 实验旨在测试GLUA1 Ser845磷酸化和突触前的作用 氯胺酮和HNK产生的快速作用抗抑郁反应中的NMDA受体作为 以及他们的地calluar和分子碱。电生理技术将合并 包括使用细胞生物学技术（例如Western blotting），包括全细胞斑块夹， 表面蛋白和Glur1 S845a敲入小鼠的生物素化，Ca1细胞或CA3细胞特异性 NR1敲除小鼠，HCN1敲除小鼠以及行为测量以实现 设计实验。拟议的项目将扩大了解理解的知识 氯胺酮快速作用抗抑郁作用的细胞机制。更好的理解 氯胺酮快速作用的抗抑郁作用将促进新一代的设计 快速作用抗抑郁药为抑郁症提供更好的疗法。