Lewis Vern, Rodrigue Brandon, Arsenault Emily, Zhang Molly, Taghavi-Abkuh Fatimeh-Frouh, Silva Weverton Castro Coelho, Myers Mysa, Matta-Camacho Edna, Aguilar-Valles Argel
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
J Neurochem. 2023 Jul;166(1):10-23. doi: 10.1111/jnc.15652. Epub 2022 Jun 25.
Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first-line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E-BP1 and 4E-BP2), are central in mediating ketamine-induced synaptic plasticity and behavioural antidepressant-like effect. 4E-BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long-lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E-BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre-clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro-cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment-resistant MDD population.
氯胺酮已在对一线治疗耐药的重度抑郁症（MDD）患者中显示出抗抑郁作用，并被批准用于该患者群体。氯胺酮可诱导多种形式的突触可塑性，这些可塑性被认为是其抗抑郁作用的基础。然而，直接导致氯胺酮抗抑郁作用的分子作用机制仍在积极研究中。最近有研究表明，雷帕霉素复合物1（mTORC1）信号通路的效应器，即真核起始因子4E（eIF4E）结合蛋白1和2（4E-BP1和4E-BP2），在介导氯胺酮诱导的突触可塑性和行为抗抑郁样效应中起核心作用。4E-BP是一类被mTORC1失活的信使核糖核酸（mRNA）翻译抑制剂。我们观察到它们在抑制性中间神经元中的表达介导了氯胺酮在强迫游泳和新奇抑制摄食试验中的作用，以及对海马体中GABA能神经传递的持久抑制。此外，另一条在mTORC1下游调节翻译延伸的效应器途径，即真核延伸因子2激酶（eEF2K），也与氯胺酮的行为效应有关。我们将讨论氯胺酮的快速抗抑郁作用如何依赖于通过4E-BP1/2和eEF2K激活神经元mRNA翻译。此外，鉴于这些途径也调节认知功能，我们将讨论氯胺酮对MDD患者认知功能影响的证据。总体而言，临床前研究积累的数据表明mRNA翻译途径与治疗MDD的情绪症状有关。然而，尚不清楚亚麻醉剂量氯胺酮在啮齿动物中的促认知潜力是否也涉及这些途径，以及在难治性MDD患者群体中是否一致观察到这种效应。
