Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression
Clara Liao, Ethan O'Farrell, Yaman Qalieh, Neil K. Savalia, Matthew J. Girgenti, Kenneth Y. Kwan, Alex C. Kwan
bioRxiv (Cold Spring Harbor Laboratory) January 4, 2025 preprint DOI: 10.1101/2025.01.04.631335 via OpenAlex
Summary
AI-generated from the abstractA single dose of psilocybin triggers time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex of mice. Excitatory neurons showed altered genes involved in synaptic plasticity, while GABAergic neurons showed changes in genes related to mitochondrial function and metabolism. These transcriptional responses occurred in an early phase at 1-2 hours and a late phase at 72 hours after administration. Ketamine produced similar transcriptional changes. These findings suggest that psilocybin's long-term neural and behavioral effects may stem from lasting alterations in gene expression.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Male and female mice |
| Interventions | Psilocybin Ketamine |
| Duration | 72 hours after administration |
| Topics | Psilocybin |
| Keywords | Gabaergic Neuroscience Biology Excitatory postsynaptic potential |
| Citations | 3 |
| Key finding | Psilocybin produces time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex, with excitatory neurons showing synaptic plasticity-related genes and GABAergic neurons showing mitochondrial function-related genes. |
Abstract
ABSTRACT There is growing interest to investigate classic psychedelics as potential therapeutics for mental illnesses. Previous studies have demonstrated that one dose of psilocybin leads to persisting neural and behavioral changes. The durability of psilocybin’s effects suggests that there are likely alterations of gene expression at the transcriptional level. In this study, we performed single-nucleus RNA sequencing of the dorsal medial frontal cortex of male and female mice. Samples were collected at 1, 2, 4, 24, or 72 hours after psilocybin or ketamine administration and from control animals. At baseline, major excitatory and GABAergic cell types selectively express particular serotonin receptor transcripts. The psilocybin-evoked differentially expressed genes in excitatory neurons were involved in synaptic plasticity, which were distinct from genes enriched in GABAergic neurons that contribute to mitochondrial function and cellular metabolism. The effect of psilocybin on gene expression was time-dependent, including an early phase at 1-2 hours followed by a late phase at 72 hours of transcriptional response after administration. Ketamine administration produced transcriptional changes that show a high degree of correlation to those induced by psilocybin. Collectively, the results reveal that psilocybin produces time-dependent and cell-type specific changes in gene expression in the medial frontal cortex, which may underpin the drug’s long-term effects on neural circuits and behavior.