Role of mTOR and Synaptogenesis in the Actions of Rapid-Acting Antidepressants

mTOR 和突触发生在速效抗抑郁药作用中的作用

• 批准号: 8812007
• 负责人: RONALD S. DUMAN
• 金额: $ 49.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812007
• 关键词: AMPA Receptors; Address; Adverse drug effect; Adverse effects; Affect; Anhedonia; Antidepressive Agents; Behavior; Behavioral; Biochemical; Blocking Antibodies; Brain-Derived Neurotrophic Factor; Chronic; Chronic stress; Clinical; Clinical Research; Cultured Cells; DLG4 gene; Data; Disease; Dose; Economic Burden; Genetic Polymorphism; Glutamate Receptor; Glutamates; Health; Hour; Human; Infusion procedures; Ketamine; Knock-in Mouse; L-Type Calcium Channels; Link; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Molecular; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; NMDA receptor 2B; NMDA receptor antagonist; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Prefrontal Cortex; Process; Protein Biosynthesis; Proteins; Rattus; Receptor Activation; Regulation; Resistance; Rodent Model; Role; Serotonin; Signal Pathway; Signal Transduction; Sirolimus; Site; Stress; Synapses; Testing; Therapeutic; Time; Vertebral column; Viral; Viral Vector; base; behavioral response; behavioral study; depressed patient; hypocretin; inhibitor/antagonist; interdisciplinary approach; mTOR protein; monoamine; multidisciplinary; neurotrophic factor; new therapeutic target; novel; response; reuptake; small hairpin RNA; synaptic function; synaptogenesis; transmission process; treatment response; treatment strategy; voltage

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is one of the most prevalent and debilitating illnesses world wide, affecting 17 percent of the population and causing enormous personal and economic burden. The impact of MDD is underscored by the limitations of currently available medications, including low response rates, treatment resistant patients, and time-lag (weeks to months) for response. These data highlight the major unmet need for more efficacious and faster-acting antidepressant agents. Recent studies demonstrate that a single low dose of ketamine, a glutamate-NMDA receptor antagonist, produces rapid antidepressant actions (2 hr) that last for up to 7 days in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, may represent one of the most significant findings in the field of depression over the past 2 decades. The mechanisms underlying the rapid antidepressant actions of ketamine have not been identified, and the current application addresses this issue. Preliminary studies have found that ketamine rapidly stimulates the mammalian target of rapamycin (mTOR) pathway in rat prefrontal cortex (PFC). The mTOR cascade has been implicated in the regulation of synaptic protein synthesis and activity-dependent enhancement of synaptic strength. Preliminary findings also demonstrate that ketamine rapidly increases spine number and synaptic function of PFC neurons and produces rapid antidepressant behavioral responses in rodent models. Moreover, these actions of ketamine are blocked by rapamycin, demonstrating a requirement for mTOR signaling. Based on these findings, we hypothesize that the rapid antidepressant actions of ketamine result from activation of mTOR signaling, stimulation of synaptic protein synthesis, and increased synapse/spine formation and function in the PFC. This application describes an integrated multidisciplinary approach, including molecular, biochemical, electrophysiological, morphological, and behavioral studies to test this hypothesis. Aim 1 will characterize the time course and regional localization of ketamine-stimulation of mTOR signaling, synaptic proteins, spines number, function, and behavioral response, as well as confirm the requirement for mTOR using a combination of pharmacological, viral vector, and shRNA approaches. The hypothesis that ketamine can rapidly reverse the deficits in spine number and function resulting from chronic stress exposure will also be tested. Aim 2 will determine the role of glutamate transmission and neurotrophic factor signaling, which have been implicated in activity-dependent stimulation of mTOR and induction of synaptic strength. Aim 3 will determine if novel therapeutic targets identified in Aims 1 and 2 produce rapid ketamine-like antidepressant responses or sustain the actions of a single dose of ketamine. Characterization of the signaling pathways that underlie the actions of ketamine will provide novel targets for safer, rapid-acting antidepressants and/or agents that sustain the response to ketamine.

描述（由申请人提供）：重度抑郁症 (MDD) 是世界范围内最普遍、最使人衰弱的疾病之一，影响 17% 的人口，并造成巨大的个人和经济负担。目前可用药物的局限性凸显了 MDD 的影响，包括反应率低、患者对治疗有抵抗力以及反应时间滞后（数周至数月）。这些数据凸显了对更有效、更快速起效的抗抑郁药物的主要未满足需求。最近的研究表明，单次低剂量的氯胺酮（一种谷氨酸 NMDA 受体拮抗剂）可产生快速抗抑郁作用（2 小时），对治疗耐药的患者可持续长达 7 天。这种快速作用的机制与典型的单胺再摄取抑制剂完全不同，可能是过去 20 年来抑郁症领域最重要的发现之一。氯胺酮快速抗抑郁作用的机制尚未确定，当前的申请解决了这个问题。初步研究发现，氯胺酮快速刺激大鼠前额皮质（PFC）中的哺乳动物雷帕霉素靶点（mTOR）通路。 mTOR 级联与突触蛋白合成的调节和突触强度的活性依赖性增强有关。初步研究结果还表明，氯胺酮可快速增加 PFC 神经元的脊柱数量和突触功能，并在啮齿动物模型中产生快速的抗抑郁行为反应。此外，氯胺酮的这些作用会被雷帕霉素阻断，这表明需要 mTOR 信号传导。基于这些发现，我们推测氯胺酮的快速抗抑郁作用是由于 mTOR 信号传导的激活、突触蛋白合成的刺激以及前额皮质中突触/棘的形成和功能的增加所致。该应用程序描述了一种综合的多学科方法，包括分子、生物化学、电生理学、形态学和行为研究来检验这一假设。目标 1 将描述氯胺酮刺激 mTOR 信号、突触蛋白、棘数量、功能和行为反应的时间过程和区域定位，并结合药理学、病毒载体和 shRNA 方法确认对 mTOR 的需求。氯胺酮可以迅速扭转因长期压力暴露而导致的脊柱数量和功能缺陷的假设也将得到检验。目标 2 将确定谷氨酸传输和神经营养因子信号传导的作用，这些信号与 mTOR 的活动依赖性刺激和突触强度的诱导有关。目标 3 将确定目标 1 和 2 中确定的新治疗靶点是否产生快速的氯胺酮样抗抑郁反应或维持单剂量氯胺酮的作用。氯胺酮作用下信号通路的表征将为更安全、快速起效的抗抑郁药和/或维持氯胺酮反应的药物提供新的靶点。