Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling
Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling
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DOI：
10.1038/mp.2017.241
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发表时间：
2018-04-01
影响因子：
11
通讯作者：
Collo, G.
中科院分区：
文献类型：
--
作者：
Cavalleri, L.;Pich, E. Merlo;Collo, G.
在氯胺酮抗抑郁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关键。所提出的机制涉及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的下游激活，其通过脑源性神经营养因子（BDNF）和蛋白质新合成触发雷帕霉素（mTOR）依赖性结构可塑性的哺乳动物靶标。我们评估了氯胺酮是否在多巴胺能（DA）神经元中引起类似的分子事件，已知多巴胺能神经元在情绪障碍中受到影响，使用一种新的翻译策略，涉及小鼠中脑和人类诱导多能干细胞衍生的DA神经元。在小鼠和人培养物中，暴露于氯胺酮60分钟引起树突状分支和索马大小的浓度依赖性增加，如应用后72小时所测量的。这些结构效应被mTOR复合物/信号传导抑制剂如雷帕霉素阻断。氯胺酮对p70 S6激酶的诱导揭示了mTOR激活的直接证据。氯胺酮的所有作用均被AMPA受体拮抗剂消除，并被AMPA阳性变构调节剂CX 614模拟。抑制BDNF信号传导阻止氯胺酮或CX 614诱导结构可塑性。此外，氯胺酮的作用需要功能完整的多巴胺D3受体（D3 R），因为其作用被选择性D3 R拮抗剂消除，而在D3 R敲除制剂中不存在。最后，氯胺酮代谢物（2 R，6 R）-羟基去甲氯胺酮在亚微摩尔浓度下模拟氯胺酮效应。这些数据表明，氯胺酮通过募集小鼠中脑和人诱导多能干细胞衍生的DA神经元中的AMPAR、mTOR和BDNF信号来增强结构可塑性。这些观察结果可能与氯胺酮对情绪的影响及其在体内的其他功能作用有关。
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 alpha-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.