Single-cell sequencing reveals psilocybin induces sustained cell-type specific plasticity in mouse medial prefrontal cortex

The ever-increasing burden of psychiatric disorders and limitations of current treatments have fueled enormous interest in the therapeutic potential of psychedelics. Yet how psychedelics, such as psilocybin, produce lasting therapeutic effects is unclear. Using scRNA-sequencing we identify a type of deep layer near projecting neuron that is most robustly regulated in the medial prefrontal cortex of female mice 24h after psilocybin. We show that this cell-type specificity does not align with 5-HT _2A receptor expression but is consistent with the integrated signaling via cell-type specific 5-HT receptor co-expression patterns. Cell-cell communication reveals that psilocybin also broadly suppresses GABAergic inhibition. Ultimately, psilocybin induces plasticity-related genes in subsets of excitatory neurons suggesting that psilocybin induces sustained increases in neuroplasticity in the mouse mPFC. Our findings point to L5/6NP neurons as a key mediator of psilocybin’s neuroplastic effects.