Abstract
ATP-sensitive potassium (K-ATP) channels have been shown to couple membrane electrical activity to energy metabolism in a variety of cells and are important in several physiological systems. In the brain, K-ATP channels are strongly expressed in the neuronal circuitry. The distributional profile and functional significance of K-ATP channels suggest that they may be involved in stress-induced depression. First, we showed that chronic mild stress (CMS) significantly increased the expression of hippocampal Kir6.2 and Kir6.1 subunits of K-ATP channels. Next, using Kir6.2 knockout (Kir6.2−/−) mice, we presented that Kir6.2 deficiency resulted in antidepressant-like behaviors under non-stress conditions, but aggravated depressive behaviors accompanied by the loss of CA3 neuron and the reduction of brain-derived neurotrophic factor in hippocampus under chronic stress. Finally, we demonstrated that the K-ATP channel opener iptakalim, as well as a classical antidepressant fluoxetine, can reverse CMS-induced depression-related behaviors and counteract the deleterious effects of stress on hippocampus in wild-type mice, but only partially alleviate these symptoms in Kir6.2−/− mice. Collectively, our findings demonstrate that K-ATP channels are involved in the pathogenesis of depression and may be a promising target for the therapy of depression.
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Acknowledgments
We are grateful to Drs. Susumu Seino and Takashi Miki, Kobe University, for generous donation of Kir6.2 knockout mice. We thank Mr. Jason Davis (Georgia Regents University) for help with revising the manuscript. This study was supported by the grants from the National Key Basic Research Program of China (No. 2011CB504103), the National Natural Science Foundation of China (No. 81473196), and the National Science and Technology Major Project (No. 2012ZX09304-001).
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Y. Fan and H. Kong contributed equally to this work.
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Fan, Y., Kong, H., Ye, X. et al. ATP-sensitive potassium channels: uncovering novel targets for treating depression. Brain Struct Funct 221, 3111–3122 (2016). https://doi.org/10.1007/s00429-015-1090-z
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DOI: https://doi.org/10.1007/s00429-015-1090-z