Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara, Lynette B. Naler, J. Saunders, Zirui Zhou, Rudy Toneatti, Salvador Sierra, Jennifer T Wolstenholme, Patrick M. Beardsley, George W. Huntley, Chang Lu, Javier González-Maeso
Cell Reports October 1, 2021 DOI: 10.1016/j.celrep.2021.109836 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | DOI |
| Dose | single dose |
| Topics | Neuroplasticity |
| Key points | A single dose of DOI produced fast-acting changes in frontal cortex dendritic spines and accelerated fear extinction via the 5-HT2A receptor in mice, and induced chromatin changes at synaptic gene enhancers lasting days. The authors propose that epigenomic-driven synaptic plasticity sustains psychedelics' long-lasting antidepressant action, and caution that these changes overlap with genetic loci associated with schizophrenia, depression, and ADHD. |
Abstract
SUMMARY 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.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 173
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Psychedelics and Other Psychoplastogens for Treating Mental Illness Frontiers in Psychiatry October 4, 2021
- Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin ACS Chemical Neuroscience January 11, 2023
and 168 more in the library
Cites 29
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
and 24 more in the library