Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors
Bilash, O. M., Che, A., Davoudian, P. A., Jiang, Q., Kim, H., Kwan, A. C., Liao, C., Liu, R.-J., Nothnagel, J. D., Savalia, N., Shao, L-X,, Tan, D., Wojtasiewicz, C., Woodburn, S. C.
This mouse study investigates how psilocybin affects different types of brain cells in the medial frontal cortex (mPFC; decision-making processes and judgement). The research finds that psilocybin increases dendritic spine density in both pyramidal tract (PT) and intratelencephalic (IT) neurons, but only PT neurons are essential for psilocybin's anti-stress effects through 5-HT2A receptor activation.
Abstract
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions. 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-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity. Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action