研究揭示氯胺酮抗抑鬱作用機制
作者：
小柯機器人發布時間：2020/12/18 21:28:18
加拿大麥吉爾大學Nahum Sonenberg和Argel Aguilar-Valles研究組合作取得最新進展。他們提出氯胺酮的抗抑鬱作用通過eIF4E參與細胞特異性翻譯。這一研究成果於2020年發表在國際頂尖學術期刊《自然》上。
他們顯示4E-BP1和4E-BP2是氯胺酮和（2R，6R）-HNK的抗抑鬱活性的關鍵效應子，氯胺酮誘導的海馬突觸可塑性取決於4E-BP2，在較小程度上取決於4E-BP1。據推測，氯胺酮激活皮質錐體興奮細胞中的mTORC1-4E-BP信號傳導。為了驗證這一假設，他們研究了在興奮性或抑制性神經元中缺乏4E-BP的小鼠中對氯胺酮和（2R，6R）-HNK的行為反應。藥物的抗抑鬱活性由興奮性神經元中的4E-BP2和抑制性神經元中的4E-BP1和4E-BP2介導。
值得注意的是，抑制性神經元中4E-BP2的基因缺失在強迫遊泳試驗中導致基線不動性降低，模擬了抗抑鬱作用。特異性地在抑制性神經元中缺失4E-BP2也阻止了氯胺酮誘導的海馬興奮性神經傳遞的增加，並且該效果與氯胺酮不能引起抑制性神經傳遞的長期降低有關。總體而言，他們的數據表明4E-BP對氯胺酮的抗抑鬱活性至關重要。
據介紹，對於重度抑鬱症，有效的藥物治療仍然是一項重大挑戰，因為超過30％的患者對一線治療（選擇性5-羥色胺再攝取抑制劑）有抵抗力。亞麻醉劑量的氯胺酮是一種非競爭性的N-甲基-D-天冬氨酸受體拮抗劑，在這些患者中提供了快速而持久的抗抑鬱作用，但這些作用的分子機制仍不清楚。氯胺酮已被提議通過其代謝物（2R，6R）-羥基降甲胺酮（（2R，6R）-HNK）發揮抗抑鬱作用。氯胺酮和（2R，6R）-HNK在齧齒動物中的抗抑鬱作用需要激活mTORC1激酶。mTORC1控制著各種神經元功能，特別是通過依賴於帽的起始mRNA翻譯，通過真核起始因子4E結合蛋白（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