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.
A single dose of psilocybin, whose metabolite psilocin activates 5-HT2A receptors, induces long-term genetic and functional changes in the orbitofrontal cortex (OFC) of male mice. Layer 5 pyramidal neurons showed the most significant changes, including reduced expression of glutamate receptors and genes involved in excitatory synapse formation and maintenance, consistent with decreased excitatory synaptic transmission. Parvalbumin- and Somatostatin-positive inhibitory neurons showed minimal changes. Knocking down the 5-HT2A receptor in layer 5 pyramidal neurons, but not in Parvalbumin-positive inhibitory neurons, reduced psilocybin-induced functional changes and its antidepressant effect. These results reveal cell type-specific mechanisms of psilocybin and highlight brain region differences in psychedelic effects.