Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors

Psilocybin transiently increases calcium event rates in apical dendritic tufts of pyramidal tract neurons in the mouse medial frontal cortex, an effect that parallels the drug's brain pharmacokinetics. This acute effect occurs selectively during quiet wakefulness and depends on the 5-HT2A receptor. Under normal conditions, dendritic calcium signaling predicts subsequent spine formation, but psilocybin disrupts this relationship. The findings suggest that the mechanisms linking acute dendritic activity to long-term structural plasticity differ between physiological and psychedelic-induced plasticity.

Study at a glance

Abstract

SUMMARY How psychedelics act on cortical dendrites to produce long-lasting structural plasticity remains poorly understood. Here, we characterize the effects of psilocybin on dendritic calcium dynamics in pyramidal tract neurons of the mouse medial frontal cortex. Psilocybin transiently increases calcium event rates in apical dendritic tufts over a time course that parallels the drug’s pharmacokinetics in the brain. This acute effect is brain state-dependent, occurring selectively during quiet wakefulness, and was abolished by cell type-specific deletion of the 5-HT 2A receptor. Under control conditions, dendritic calcium signaling predicts subsequent spine formation, but this relationship is not preserved following psilocybin administration. Together, these findings reveal that psilocybin engages brain state- and 5-HT 2A receptor-dependent dendritic signaling, while altering the relationship between acute dendritic activity and long-term structural plasticity. The results suggest that the mechanisms linking acute dendritic signaling to structural remodeling differ between physiological and psychedelic-induced plasticity.