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标题：Antidepressant Effects of (S)-Ketamine through a Reduction of Hyperpolarization-Activated Current I h
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作者：Chung Sub Kim ; Daniel Johnston
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：6
页码：1-48
DOI：10.1016/j.isci.2020.101239
语种：English
出版社：Elsevier
摘要：SummaryCompelling 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 currentIhof dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendriticIhin chronic unpredictable stress (CUS) rats. The reduction ofIhby (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 vivoinfusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functionalIh, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or preventsIhfrom being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.Graphical AbstractDisplay OmittedHighlights•(S)-ketamine reduced the CUS-induced upregulation of somaticIh•This was independent of NMDAR, Ba2+-sensitive conductances, and cAMP signaling•(S)-ketamine pretreatment before the onset of depression provided resiliency to CUS•In vivothapsigargin-induced changes in behaviors were reversed by (S)-ketamineNeuroscience; Behavioral Neuroscience; Cellular Neuroscience