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.