BACKGROUND Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. METHODS To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice. We analyzed the effects biochemically and behaviorally, using the forced swim, tail suspension, and novelty suppressed feeding tests. RESULTS Consistent with the literature, one of the major pathways mediating the antidepressant action of ketamine was reduction of phosphorylation of eEF2 via eEF2K. Specifically, knocking out eEF2K in mice eliminated phosphorylation of eEF2 at threonine at position 56, resulting in increased protein synthesis, and made mice resistant both biochemically and behaviorally to the antidepressant effects of ketamine. In addition, administration of ketamine led to differential regulation of CaMKII function, manifested as autoinhibition (pT305 phosphorylation) followed by autoactivation (pT286) of CaMKIIα in the hippocampus and cortex. The inhibition phase of CaMKII, which lasted 10 to 20 minutes after administration of ketamine, occurred concurrently with eEF2K-dependent increased protein synthesis. Moreover, ketamine administration-dependent delayed induction of GluA1 (24 hours) was regulated by the activation of CaMKII. Importantly, systemic administration of the CaMKII inhibitor tatCN21 increased global protein synthesis and induced behavioral resistance to ketamine. CONCLUSIONS Our data suggest that drugs that selectively target CaMKs and regulate protein synthesis offer novel strategies for treatment of major depressive disorder.

中文翻译：

---

CaMKII 和 eEF2K 通路介导氯胺酮的抗抑郁作用

背景氯胺酮是一种 N-甲基-D-天冬氨酸受体拮抗剂，给药后可在重度抑郁症患者中产生快速抗抑郁反应。然而，氯胺酮抗抑郁作用的机制尚不清楚。方法为了阐明氯胺酮的作用机制，我们用钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 特异性抑制剂 tatCN21 肽处理野生型 C57BL/6 小鼠。我们还使用了真核延伸因子 2 激酶 (eEF2K)（也称为 CaMKIII）基因敲除小鼠。我们使用强制游泳、悬尾和新奇抑制喂养测试从生化和行为上分析了影响。结果 与文献一致，介导氯胺酮抗抑郁作用的主要途径之一是通过 eEF2K 减少 eEF2 的磷酸化。具体而言，敲除小鼠中的 eEF2K 消除了 eEF2 在第 56 位苏氨酸处的磷酸化，导致蛋白质合成增加，并使小鼠在生化和行为上对氯胺酮的抗抑郁作用产生抗药性。此外，氯胺酮的给药导致 CaMKII 功能的差异调节，表现为海马和皮层中 CaMKIIα 的自抑制（pT305 磷酸化）和自激活（pT286）。CaMKII 的抑制阶段在施用氯胺酮后持续 10 至 20 分钟，与 eEF2K 依赖性增加的蛋白质合成同时发生。此外，氯胺酮给药依赖性延迟诱导 GluA1（24 小时）受 CaMKII 激活的调节。重要的，CaMKII 抑制剂 tatCN21 的全身给药增加了整体蛋白质合成并诱导了对氯胺酮的行为抵抗。结论 我们的数据表明，选择性靶向 CaMK 并调节蛋白质合成的药物为治疗重度抑郁症提供了新的策略。