Role of mTOR and synaptic protein synthesis in the rapid antidepressant actions o

描述（由申请人提供）：重度抑郁症（MDD）是世界上最普遍和最令人衰弱的疾病之一，影响了17%的人口，造成了巨大的个人和经济负担。目前可用药物的局限性强调了重度抑郁症的影响，包括低反应率、耐药患者和反应滞后（几周到几个月）。这些数据突出了对更有效和更快速的抗抑郁药物的主要未满足需求。最近的研究表明，单次低剂量氯胺酮（一种谷氨酸- nmda受体拮抗剂）可在治疗耐药患者中产生快速的抗抑郁作用（2小时），并持续长达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，目前的应用解决了这个问题。初步研究发现氯胺酮能快速刺激大鼠前额叶皮层（PFC）雷帕霉素（mTOR）通路的哺乳动物靶点。mTOR级联涉及突触蛋白合成的调节和突触强度的活性依赖性增强。在啮齿类动物模型中，氯胺酮能迅速增加PFC神经元的脊柱数目和突触功能，并产生快速的抗抑郁行为反应。此外，氯胺酮的这些作用被雷帕霉素阻断，表明需要mTOR信号传导。基于这些发现，我们假设氯胺酮的快速抗抑郁作用是由于mTOR信号的激活，突触蛋白合成的刺激，以及pfc中突触/脊柱形成和功能的增加。这一应用描述了一个综合的多学科方法，包括分子、生化、电生理、形态学和行为学研究来验证这一假设。目的1将描述氯胺酮刺激mTOR信号、突触蛋白、棘数、功能和行为反应的时间过程和区域定位，并使用药理学、病毒载体和shRNA方法的组合来确认mTOR的必要性。氯胺酮可以迅速逆转慢性应激暴露导致的脊柱数量和功能缺陷的假设也将得到验证。目的2将确定谷氨酸传递和神经营养因子信号的作用，这与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和目标2中确定的新治疗靶点是否产生类似氯胺酮的快速抗抑郁反应或维持单剂量氯胺酮的作用。氯胺酮作用的信号通路的特征将为更安全、快速的抗抑郁药和/或维持对氯胺酮反应的药物提供新的靶点。

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. PUBLIC HEALTH RELEVANCE: Depression is one of the most prevalent and debilitating illnesses world wide, and the personal and economic burdens of this disorder are underscored by the lack of rapid, safe, and efficacious medications. Recent clinical studies demonstrate that a glutamate-NMDA receptor antagonist, ketamine, produces rapid antidepressant therapeutic responses within hours of treatment and that last for up to 7 days in patients who are resistant to typical antidepressants. Studies are described to identify the cellular signaling mechanisms underlying the rapid antidepressant actions of ketamine, and to utilize this information to test novel therapeutic targets with potential for rapid and efficacious treatment response rates, without the side effects of ketamine, and thereby address a major unmet need for the treatment of depression.