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Cited by 224Psychedelics and Drug StudiesTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

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de la Fuente Revenga, Mario, Zhu, Bohan, Guevara, Christopher A., Naler, Lynette B., Saunders, Justin M., Zhou, Zirui, Toneatti, Rudy, Sierra, Salvador +5 more·2021·Cell Reports
DOI 10.1016/j.celrep.2021.109836PMC PMC8582597
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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-HT 2A 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.

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  • DOI treatment (2 mg/kg) increases the density of stubby and thin, but not mushroom, spines on cortical neurons in the mouse frontal cortex.

    “DOI treatment (2 mg/kg) increases the density of stubby and thin, but not mushroom, spines on cortical neurons in the mouse frontal cortex; it also enhances LTP at synapses onto these neurons (de la Fuente Revenga et al., 2021).”

    From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as de la Fuente Revenga et al., 2021

    The Results section reports that a single DOI administration increased stubby and thin spine density, but not mushroom spine density, in mouse frontal-cortex neurons. The Methods specify 2 mg/kg DOI for other assays, including LTP recordings, but the passages found do not explicitly tie that dose to the spine-density experiment. No page numbers were available in our copy. (LLM, conf=0.78)

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  • DOI treatment (2 mg/kg) enhances LTP at synapses onto cortical neurons in the mouse frontal cortex.

    “DOI treatment (2 mg/kg) increases the density of stubby and thin, but not mushroom, spines on cortical neurons in the mouse frontal cortex; it also enhances LTP at synapses onto these neurons (de la Fuente Revenga et al., 2021).”

    From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as de la Fuente Revenga et al., 2021

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Authors
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.
Affiliations
  • Virginia Tech (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Virginia Commonwealth University (US)
Corresponding author
Lu, Chang
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-10
Volume
37
Issue
3
Pages
109836
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.109836
PMC
PMC8582597
OpenAlex
W3205085416
Cited by
224
References
18
Citations by year
2026: 47 · 2025: 47 · 2024: 53 · 2023: 34 · 2022: 34 · 2021: 9
FWCI
22.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • VTechWorks (Virginia Tech) (submittedVersion, cc-by-nc-nd)
Funders
National Institutes of Health (N01DA-19-8949, R01NS107512, T32MH087004, N01DA-17-8932, T32MH020030, P50AA022537, F30MH116550, R01MH084894, P30DA033934, R01MH111940, R01GM143940)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
psychedelics, digital object identifiers, 5-HT2A receptor, epigenomics, chromatin organization, enhancers, dendritic spines, synaptic plasticity, fear extinction, antidepressant effects, single-dose exposure, schizophrenia, depression, attention deficit hyperactivity disorder, frontal cortex
MeSH terms
Epigenome, Amphetamines, Animals, Behavior, Animal, Extinction, Psychological, Fear, Frontal Lobe, Hallucinogens, Male, Mice, Inbred C57BL, Neuronal Plasticity, Synapses, Time Factors, Mice, Knockout, Epigenesis, Genetic, Receptor, Serotonin, 5-HT2A, Dendritic Spines, Mice, Mice, 129 Strain, Epigenomics, Serotonin 5-HT2 Receptor Agonists

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