CircKat6b Mediates the Antidepressant Effect of Esketamine by Regulating Astrocyte Function.
Molecular neurobiology – February 01, 2025
Source: PubMed
Summary
Groundbreaking research reveals how esketamine, a promising antidepressant, works in the brain. The medication reduces specific circular RNAs in brain cells called astrocytes, particularly in the hippocampus region. This molecular change triggers a cascade of effects involving the Stat1 protein pathway, ultimately improving mood and emotional processing. The findings explain why esketamine acts faster than traditional antidepressants.
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.