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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male and female mice |
| Interventions | Psilocybin Ketamine |
| Duration | 72 hours after administration |
| Topics | Psilocybin |
| Keywords | Gabaergic Excitatory postsynaptic potential Gene expression Transcriptome Hallucinogen |
| Citations | 3 |
| Key findings | 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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 4
- The ABCs of psychedelics: a preclinical roadmap for drug discovery. TIPS - Trends in Pharmacological Sciences August 28, 2025
- Psychedelic Modulation of Excitation/Inhibition Balance: A Dual-Phase Neurodevelopmental Model. ACS Chemical Neuroscience January 7, 2026
- Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic exposure. bioRxiv : the preprint server for biology January 16, 2025
- Mapping excitatory synaptic plasticity evoked by single-dose psilocybin in mice