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.
Ketamine increased glucose uptake and GLUT3 expression in the prefrontal cortex of female mice with depressive-like behaviors, and this effect depended on activation of the ERK signaling pathway. Mice treated with ketamine showed higher glucose uptake, more lactate production, and shorter immobility time compared to untreated depressed mice. An ERK1/2 inhibitor blocked these ketamine-induced changes, indicating that the ERK/GLUT3 pathway mediates ketamine's antidepressant-like effects on brain energy metabolism.