Antidepressant actions of ketamine engage cell-specific translation via eIF4E
Antidepressant actions of ketamine engage cell-specific translation via eIF4E
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DOI：
10.1038/s41586-020-03047-0
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发表时间：
2020-12-16
期刊：
影响因子：
64.8
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Aguilar-Valles, Argel;De Gregorio, Danilo;Sonenberg, Nahum
重度抑郁症的有效药物治疗仍然是一个重大挑战，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）具有耐药性（1）。亚麻醉剂量的氯胺酮（一种非竞争性N-甲基-d-天冬氨酸受体拮抗剂（2，3））在这些患者中提供了快速和持久的抗抑郁作用（4-6），但这些作用的分子机制仍不清楚（7，8）。已提出氯胺酮通过其代谢产物（2 R，6 R）-羟基去甲氯胺酮（（2 R，6 R）-HNK）发挥其抗抑郁作用（9）。氯胺酮和（2 R，6 R）-HNK在啮齿类动物中的抗抑郁作用需要激活mTORC 1激酶（10，11）。mTORC 1控制各种神经元功能（12），特别是通过真核起始因子4 E结合蛋白（4 E-BP）的磷酸化和失活，通过帽依赖性启动mRNA翻译（13）。在这里，我们表明，4 E-BP 1和4 E-BP 2是氯胺酮和（2 R，6 R）-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依赖于4 E-BP 2，并在较小程度上依赖于4 E-BP 1。据推测，氯胺酮可激活皮质锥体兴奋细胞中的mTORC 1 - 4 E-BP信号传导（8，1 - 4）。为了验证这一假设，我们研究了兴奋性或抑制性神经元中缺乏4 E-BP的小鼠对氯胺酮和（2 R，6 R）-HNK的行为反应。这些药物的抗抑郁活性在兴奋性神经元中由4 E-BP 2介导，在抑制性神经元中由4 E-BP 1和4 E-BP 2介导。值得注意的是，抑制性神经元中4 E-BP 2的遗传缺失诱导了强迫游泳试验中基线不动性的降低，模拟了抗抑郁作用。在抑制性神经元中特异性地缺失4 E-BP 2也阻止了氯胺酮诱导的海马兴奋性神经传递的增加，并且这种作用与氯胺酮不能诱导抑制性神经传递的持久减少一致。总体而言，我们的数据表明，4 E-BP是氯胺酮抗抑郁活性的核心。氯胺酮在小鼠中的抗抑郁样作用取决于兴奋性和抑制性神经元中特异性eIF 4 E结合蛋白的表达。
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 antagonist(2,3), provide rapid and long-lasting antidepressant effects in these patients(4-6), but the molecular mechanism of these effects remains unclear(7,8). 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 kinase(10,11). mTORC1 controls various neuronal functions(12), 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 cortex(8,14). 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.The antidepressant-like effects of ketamine in mice depend on the expression of specific eIF4E-binding proteins in excitatory and inhibitory neurons.