Abstract：
The abundant expression of circular RNAs (circRNAs) in the central nervous system and their contribution to the pathogenesis of depression suggest that circRNAs are promising therapeutic targets for depression. This study explored the role and mechanism of circKat6b in esketamine\'s antidepressant effect. We found that intravenous administration of esketamine (5 mg/kg) treatment decreased the circKat6b expression in the astrocytes of hippocampus induced by a chronic unpredictable mild stress (CUMS) mouse model, while the overexpression of circKat6b in the hippocampus significantly attenuated the antidepressant effects of esketamine in depressed mice. RNA-sequencing, RT-PCR, and western blot experiments showed that the stat1 and p-stat1 expression were significantly upregulated in mouse astrocytes overexpressing circKat6b. In the CUMS mouse model, overexpression of circKat6b in the hippocampus significantly reversed the downregulation of p-stat1 protein expression caused by esketamine. Our findings demonstrated that a novel mechanism of the antidepressant like effect of esketamine may be achieved by reducing the expression of circKat6b in the astrocyte of the hippocampus of depressed mice.
摘要：
环状RNA（circularRNAs，circRNAs）在中枢神经系统中的丰富表达及其对抑郁症发病机制的贡献表明，circRNAs是有希望的抑郁症治疗靶点。本研究探讨circKat6b在艾氯胺酮抗抑郁作用中的作用及机制。我们发现，静脉注射艾氯胺酮（5mg/kg）治疗降低了由慢性不可预测的轻度应激（CUMS）小鼠模型诱导的海马星形胶质细胞中的circkat6b表达，而海马中circKat6b的过表达显着减弱了esketamine在抑郁小鼠中的抗抑郁作用。RNA测序，RT-PCR,和westernblot实验表明，stat1和p-stat1表达在过表达circKat6b的小鼠星形胶质细胞中显著上调。在CUMS鼠标模型中，海马中circKat6b的过度表达显著逆转了由esketamine引起的p-stat1蛋白表达的下调。我们的发现表明，通过减少抑郁小鼠海马星形胶质细胞中circKat6b的表达，可以实现艾氯胺酮抗抑郁样作用的新机制。
