Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action
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
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2024 preprint DOI: 10.1101/2024.11.02.621692 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo optical imaging, chemogenetic perturbation, and cell type-specific electrophysiology |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | a single dose |
| Topics | Depression Psilocybin Serotonin |
| Keywords | Neural networks Neurobiology Mood disorders Psychiatric treatment Dendritic spines Frontal cortex Structural plasticity Psychedelics hallucinogens Entheogens Neuroscience brain science Mental health depression |
| Key points | Silencing PT neurons, but not IT neurons, eliminates psilocybin's ability to ameliorate stress-related phenotypes, and targeted knockout of 5-HT2A receptors abolishes psilocybin's effects on stress-related behavior and structural plasticity. |
Abstract
Abstract 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 remodeling 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 psychedelics’ behavioral 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 increased the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviorally, 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 behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT 2A receptor in the medial frontal cortex as playing essential roles for psilocybin’s long-term drug action.