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, Alex C Kwan
Nature June 1, 2025 DOI: 10.1038/s41586-025-08813-6 via PubMed
Summary
AI-generated from the abstractA single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
Study at a glance
| Characteristics | Experimental study with in vivo optical imaging, chemogenetic perturbation, and cell-type-specific electrophysiology Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | a single dose |
| Keywords | Neuroscience Psychedelics Mental health Brain research Stress disorders |
| Citations | 75 |
| Key finding | Psilocybin's long-term effects on stress-related behavior and structural plasticity depend on PT neurons and the 5-HT2A receptor in the medial frontal cortex. |
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.