加拿大麦吉尔大学Nahum Sonenberg和Argel Aguilar-Valles研究组合作取得最新进展。他们提出氯胺酮的抗抑郁作用通过eIF4E参与细胞特异性翻译。这一研究成果于2020年发表在国际顶尖学术期刊《自然》上。
他们显示4E-BP1和4E-BP2是氯胺酮和（2R，6R）-HNK的抗抑郁活性的关键效应子，氯胺酮诱导的海马突触可塑性取决于4E-BP2，在较小程度上取决于4E-BP1。据推测，氯胺酮激活皮质锥体兴奋细胞中的mTORC1-4E-BP信号传导。为了验证这一假设，他们研究了在兴奋性或抑制性神经元中缺乏4E-BP的小鼠中对氯胺酮和（2R，6R）-HNK的行为反应。药物的抗抑郁活性由兴奋性神经元中的4E-BP2和抑制性神经元中的4E-BP1和4E-BP2介导。
值得注意的是，抑制性神经元中4E-BP2的基因缺失在强迫游泳试验中导致基线不动性降低，模拟了抗抑郁作用。特异性地在抑制性神经元中缺失4E-BP2也阻止了氯胺酮诱导的海马兴奋性神经传递的增加，并且该效果与氯胺酮不能引起抑制性神经传递的长期降低有关。总体而言，他们的数据表明4E-BP对氯胺酮的抗抑郁活性至关重要。
据介绍，对于重度抑郁症，有效的药物治疗仍然是一项重大挑战，因为超过30％的患者对一线治疗（选择性5-羟色胺再摄取抑制剂）有抵抗力。亚麻醉剂量的氯胺酮是一种非竞争性的N-甲基-D-天冬氨酸受体拮抗剂，在这些患者中提供了快速而持久的抗抑郁作用，但这些作用的分子机制仍不清楚。氯胺酮已被提议通过其代谢物（2R，6R）-羟基降甲胺酮（（2R，6R）-HNK）发挥抗抑郁作用。氯胺酮和（2R，6R）-HNK在啮齿动物中的抗抑郁作用需要激活mTORC1激酶。mTORC1控制着各种神经元功能，特别是通过依赖于帽的起始mRNA翻译，通过真核起始因子4E结合蛋白（4E-BPs）的磷酸化和失活。
附：英文原文
Title: Antidepressant actions of ketamine engage cell-specific translation via eIF4E
Author: Argel Aguilar-Valles, Danilo De Gregorio, Edna Matta-Camacho, Mohammad J. Eslamizade, Abdessattar Khlaifia, Agnieszka Skaleka, Martha Lopez-Canul, Angelica Torres-Berrio, Sara Bermudez, Gareth M. Rurak, Stephanie Simard, Natalina Salmaso, Gabriella Gobbi, Jean-Claude Lacaille, Nahum Sonenberg
Issue&Volume: 2020-12-16
Abstract: Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4,5,6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1–4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.
DOI: 10.1038/s41586-020-03047-0
Source: https://www.nature.com/articles/s41586-020-03047-0
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
