Psilocybin modulates the nucleus accumbens activity via astrocytic transcriptional regulation
Psilocybin, a classical psychedelic compound with emerging therapeutic potential for mood and addiction disorders, exerts poorly understood effects at the cellular and circuit levels. Here, we demonstrate that psilocybin engages a previously unrecognized astrocytic transcriptionally regulated mechanism of inhibitory gliotransmission within the nucleus accumbens (NAc). Using a multiscale approach combining drug discrimination, in vivo electrophysiology, microdialysis, transcriptomics, and in vitro cell-type-specific assays, we found that psilocybin enhanced NAc excitability by reducing GABAergic tone. Transcriptomic and biochemical analyses identified NFATc4 as a psilocybin-responsive molecule, accompanied by increased histone acetylation (H3K27ac). Notably, these chromatin-state modifications were confined to astrocytes, with no detectable neuronal involvement. Functional assays further confirmed that psilocybin selectively suppressed GABA synthesis in astrocytes, linking NFATc4-H3K27ac modulation to reduced inhibitory gliotransmission and enhanced neuronal activity in the NAc. These findings identify astrocytes as key mediators of psychedelic action and suggest an epigenetic modulation mediated by histone acetylation. By linking psilocybin-induced astrocytic histone modification to altered inhibitory control within the NAc, this study provides a mechanistic foundation for future glia-targeted and psychedelic-based therapeutic approaches. These findings uncover an astrocytic chromatin axis underlying the psychoactive actions of psilocybin, redefining the cellular basis of psychedelic modulation