Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.

中文翻译：

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氯胺酮通过 AMPAR 驱动的 BDNF 和 mTOR 信号传导增强小鼠中脑和人 iPSC 衍生的多巴胺能神经元的结构可塑性。

在氯胺酮抗抑郁特性的神经生物学机制中，前额叶和海马神经元的结构重塑被认为是至关重要的。建议的机制涉及 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体的下游激活，该受体通过脑源性神经营养因子 (BDNF) 触发哺乳动物雷帕霉素靶标 (mTOR) 依赖性结构可塑性和蛋白质新合成。我们使用一种涉及小鼠中脑和人类诱导的多能干细胞衍生的 DA 神经元的新型转化策略，评估了氯胺酮是否会在已知受情绪障碍影响的多巴胺能 (DA) 神经元中引发类似的分子事件。60 分钟暴露于氯胺酮会引起小鼠和人类培养物中树突状树枝状结构和体细胞大小的浓度依赖性增加，这是在应用后 72 小时测量的。这些结构效应被雷帕霉素等 mTOR 复合物/信号抑制剂阻断。通过诱导 p70S6 激酶揭示了氯胺酮激活 mTOR 的直接证据。氯胺酮的所有作用都被 AMPA 受体拮抗剂消除，并被 AMPA 阳性变构调节剂 CX614 模拟。BDNF 信号传导的抑制阻止了氯胺酮或 CX614 对结构可塑性的诱导。此外，氯胺酮的作用需要功能完整的多巴胺 D3 受体 (D3R)，因为其作用被选择性 D3R 拮抗剂消除并且在 D3R 敲除制剂中不存在。最后，氯胺酮代谢物（2R，6R)-羟基去甲氯胺酮在亚微摩尔浓度下模拟氯胺酮作用。这些数据表明，氯胺酮通过在小鼠中脑和人类诱导的多能干细胞衍生的 DA 神经元中募集 AMPAR、mTOR 和 BDNF 信号传导来引发结构可塑性。这些观察结果可能与氯胺酮对情绪的影响及其体内其他功能作用有关。