Psilocybin's lasting action requires pyramidal cell types and 5-HT<sub>2A</sub> receptors.
Abstract
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses<sup>1-4</sup>. At the cellular level, psychedelics induce structural neural plasticity<sup>5,6</sup>, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells<sup>7-9</sup>. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics' behavioural actions<sup>10</sup>. 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<sub>2A</sub> 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<sub>2A</sub> receptor in the medial frontal cortex have essential roles in psilocybin's long-term drug action.
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