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.
A single dose of psilocybin, a psychedelic whose metabolite psilocin activates 5-HT2A receptors, induces long-term genetic and functional changes in neurons of the orbitofrontal cortex (OFC), a brain region implicated in depression and other psychological disorders. Excitatory and inhibitory neurons together reduce circuit activity in the OFC. Knocking down the 5-HT2A receptor in deep-layer excitatory neurons diminishes these functional changes and the anti-depressant effect. These findings reveal cell type-specific mechanisms of psilocybin and highlight differences in how psychedelics affect distinct brain regions.