Kim Chung Sub, Johnston Daniel
Center for Learning and Memory and Department of Neuroscience, University of Texas at Austin, 1 University Station Stop, C7000, Austin, TX 78712, USA.
Center for Learning and Memory and Department of Neuroscience, University of Texas at Austin, 1 University Station Stop, C7000, Austin, TX 78712, USA.
iScience. 2020 Jun 26;23(6):101239. doi: 10.1016/j.isci.2020.101239. Epub 2020 Jun 4.
Compelling evidence suggests that a single sub-anesthetic dose of (R,S)-ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanisms underlying the antidepressant effects of (R,S)-ketamine remain unclear. Here, we show that (S)-ketamine reduced dendritic but not somatic hyperpolarization-activated current I of dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendritic I in chronic unpredictable stress (CUS) rats. The reduction of I by (S)-ketamine was independent of NMDA receptors, barium-sensitive conductances, and cAMP-dependent signaling pathways in both unstressed and CUS groups. (S)-ketamine pretreatment before the onset of depression prevented CUS-induced behavioral phenotypes and neuropathological changes of dorsal CA1 neurons. Finally, in vivo infusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functional I, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or prevents I from being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.
有力证据表明，单次亚麻醉剂量的（R,S）-氯胺酮能产生快速且显著的抗抑郁作用。然而，（R,S）-氯胺酮抗抑郁作用的细胞机制仍不清楚。在此，我们表明，（S）-氯胺酮降低了未受应激大鼠背侧海马CA1区神经元树突而非胞体的超极化激活电流I，而在慢性不可预测应激（CUS）大鼠中，（S）-氯胺酮同时降低了胞体和树突的I。在未受应激和CUS组中，（S）-氯胺酮对I的降低均独立于NMDA受体、钡敏感电导和cAMP依赖性信号通路。在抑郁发作前进行（S）-氯胺酮预处理可预防CUS诱导的行为表型以及背侧海马CA1区神经元的神经病理变化。最后，体内注入毒胡萝卜素可诱导焦虑样和快感缺失样行为以及功能性I的上调，但这些均被（S）-氯胺酮逆转。我们的结果表明，（S）-氯胺酮可减少或防止CUS后I的增加，这有助于其快速抗抑郁作用以及对CUS的恢复力。
