Cell-type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex

Despite enormous interest in psychedelics for psychiatric interventions, potential underlying biological mechanisms remain unclear. Here, we confirm that a single dose of psilocybin increases synaptic transmission in mouse medial prefrontal cortex. Using scRNA-sequencing, we identify cell-type specific mechanisms of sustained neuroplastic effects. We show that, 24h post-psilocybin, expression of plasticity-related genes is increased in excitatory neurons and that transcription in a type of deep layer near projecting neuron, L5/6 NP, is robustly altered. Analyzing receptor expression patterns reveals that this cell-type specificity does not align with 5-HT2A expression but aligns with 5-HT2C expression patterns. Further, multivariate analyses identify psilocybin-induced gene expression patterns in L5/6 NP neurons predict 5-HT2C, but not 5-HT2A, transcript levels. Pharmacologic manipulation with a 5-HT2C antagonist attenuates the post-acute sustained effect of psilocybin on synaptic transmission, highlighting 5-HT2C signaling and L5/6 NP neurons as key mediators of psychedelic drug action’s sustained neuroplastic effects in mPFC.