Psilocybin's lasting action requires pyramidal cell types and 5-HT(2A) receptors.

Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses(1-4). At the cellular level, psychedelics induce structural neural plasticity(5,6), exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells(7-9). A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics' behavioural actions(10). Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviourally, silencing the PT neurons eliminates psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT(2A) receptors abolishes psilocybin's effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT(2A) receptor in the medial frontal cortex have essential roles in psilocybin's long-term drug action.