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

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17%的人口，造成巨大的个人和经济负担。MDD的影响突出表现在目前可用药物的局限性，包括低应答率、耐药患者和应答时滞（数周至数月）。这些数据突出了对更有效和更快起效的抗抑郁药的主要未满足需求。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）可在治疗抵抗患者中产生快速的抗抑郁作用（2小时），持续长达7天。这种快速的作用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，目前的申请解决了这一问题。初步研究发现，氯胺酮可快速刺激大鼠前额叶皮层（PFC）中的哺乳动物雷帕霉素靶蛋白（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，氯胺酮迅速增加PFC神经元的棘数和突触功能，并在啮齿动物模型中产生快速的抗抑郁行为反应。此外，氯胺酮的这些作用被雷帕霉素阻断，表明需要mTOR信号传导。基于这些研究结果，我们假设氯胺酮的快速抗抑郁作用是由mTOR信号传导的激活、突触蛋白合成的刺激以及PFC中突触/棘形成和功能的增加引起的。本申请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、形态学和行为学研究来验证这一假设。目的1将表征氯胺酮刺激mTOR信号传导、突触蛋白、棘数量、功能和行为反应的时间过程和区域定位，以及使用药理学、病毒载体和shRNA方法的组合来确认对mTOR的需求。还将检验氯胺酮可快速逆转慢性应激暴露导致的脊柱数量和功能缺陷的假设。目的2将确定谷氨酸传递和神经营养因子信号传导的作用，这与mTOR的活性依赖性刺激和突触强度的诱导有关。目的3将确定目的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。表征氯胺酮作用的信号通路将为更安全、速效的抗抑郁药和/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.