CircKat6b Mediates the Antidepressant Effect of Esketamine by Regulating Astrocyte Function.

Circular RNAs (circRNAs) are abundant in the central nervous system and linked to depression. In a mouse model of depression (chronic unpredictable mild stress), a single intravenous dose of esketamine (5 mg/kg) reduced the expression of circKat6b in hippocampal astrocytes. Overexpressing circKat6b in the hippocampus weakened esketamine's antidepressant effects. Molecular analyses revealed that circKat6b overexpression increased stat1 and p-stat1 expression in astrocytes, and reversed esketamine's suppression of p-stat1. The findings suggest esketamine's antidepressant action may involve lowering circKat6b in hippocampal astrocytes.

Study at a glance

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.