Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors

Ling-Xiao Shao, Clara Liao, Pasha A. Davoudian, Neil K. Savalia, Quan Jiang, Cassandra Wojtasiewicz, Diran Tan, Jack D. Nothnagel, Rong-Jian Liu, Samuel C. Woodburn, Olesia M. Bilash, Hail Kim, Alicia Che and Alex C. Kwan ()
Additional contact information
Ling-Xiao Shao: Cornell University
Clara Liao: Cornell University
Pasha A. Davoudian: Cornell University
Neil K. Savalia: Cornell University
Quan Jiang: Cornell University
Cassandra Wojtasiewicz: Cornell University
Diran Tan: Cornell University
Jack D. Nothnagel: Cornell University
Rong-Jian Liu: Yale University School of Medicine
Samuel C. Woodburn: Cornell University
Olesia M. Bilash: Cornell University
Hail Kim: KAIST
Alicia Che: Yale University School of Medicine
Alex C. Kwan: Cornell University

Nature, 2025, vol. 642, issue 8067, 411-420

Abstract: Abstract Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1–4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7–9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions10. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08813-6

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