Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression
OpenAlex – January 04, 2025
Source: OpenAlex
Summary
Psilocybin, a hallucinogen, profoundly alters brain Biology, a key Neuroscience finding. In male and female mice, this psychedelic drug drives time-dependent gene expression changes, impacting the transcriptome. Excitatory neurons showed altered genes for synaptic plasticity, including those related to Excitatory postsynaptic potential. GABAergic neurons exhibited shifts in mitochondrial function genes. These Psychedelics and Drug Studies suggest a Neurotransmitter Receptor Influence on Behavior, explaining psilocybin's lasting effects relevant to Tryptophan and brain disorders. Ketamine produced similar gene expression shifts.
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.