Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice
This rodent study investigated the biological substrates of the enduring effects of the psychedelic DOI on the frontal cortex. It finds that a single dose produced rapid structural changes in dendritic spines and sustained alterations in chromatin organisation related to synaptic plasticity, potentially explaining long-lasting antidepressant actions.
Authors
- De La, M.
- Revenga, F.
- Zhu, B.
Published
Abstract
Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.
Research Summary of 'Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice'
Introduction
Depressive, anxiety and stress-related disorders are highly prevalent and current pharmacotherapies, including monoamine reuptake inhibitors, are limited by delayed onset of action and a substantial proportion of treatment resistance. Psychedelic compounds (phenethylamines such as DOI and mescaline, and tryptamines such as psilocybin and DMT) produce marked acute alterations in perception and cognition, and recent clinical pilot studies have reported rapid and sometimes long-lasting improvements in mood and anxiety measures following single administrations. Despite promising clinical signals, the molecular mechanisms that might underlie durable antidepressant-like effects of psychedelics—and whether these rely on the same receptor targets implicated in acute hallucinogenic effects—remain incompletely understood. This study set out to characterise post-acute molecular and synaptic plasticity changes in mouse frontal cortex following a single systemic dose of the phenethylamine psychedelic DOI, and to test the extent to which those changes depend on the serotonin 5-HT 2A receptor (5-HT 2A R). The investigators combined behavioural assays relevant to depression, anxiety and fear learning with dendritic spine imaging, electrophysiological measures of synaptic plasticity, cell-type-specific epigenomic profiling (H3K27ac ChIP-seq) and RNA-seq from neuronal nuclei, and computational analyses including enhancer clustering, motif and gene-network analysis. The goal was to link persistent chromatin and synaptic alterations to lasting behavioural effects observed after the drug has been cleared from brain tissue.
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Study Details
- Study Typeindividual
- Journal
- Topics
- APA Citation
de la Fuente Revenga, M., Zhu, B., Guevara, C. A., Naler, L. B., Saunders, J. M., Zhou, Z., Toneatti, R., Sierra, S., Wolstenholme, J. T., Beardsley, P. M., Huntley, G. W., Lu, C., & González-Maeso, J. (2021). Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Reports, 37(3), 109836. https://doi.org/10.1016/j.celrep.2021.109836
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