Prolonged epigenetic 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, Justin M. Saunders, Zirui Zhou, Rudy Toneatti, Salvador Sierra, Jennifer T Wolstenholme, Patrick M. Beardsley, George W. Huntley, Chang Lu, Javier González-Maeso
bioRxiv (Cold Spring Harbor Laboratory) February 25, 2021 preprint DOI: 10.1101/2021.02.24.432725 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Intervention | DOI |
| Dose | single dose |
| Topics | Neuroplasticity |
| Keywords | Antidepressant Epigenetics Psychosis Schizophrenia object-oriented programming Chromatin Epigenome Extinction optical mineralogy Receptor Hippocampus Dna methylation |
| Citations | 11 |
| Key findings | A single dose of DOI induces lasting changes in chromatin organization at enhancer regions of synaptic assembly genes via the 5-HT2A receptor, driving synaptic plasticity and fear extinction, which may explain its rapid antidepressant action, while also overlapping with genetic risk loci for psychiatric disorders. |
Abstract
Clinical evidence suggests a potential therapeutic effect of classic psychedelics for the treatment of depression. The most outstanding and distinct characteristic is the rapid and sustained antidepressant action with one single exposure to the drug. However, the biological substrates and key mediators of psychedelics’ enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produced 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 led to changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure. DOI-induced alterations in neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression and attention deficit hyperactivity disorder. Together, these data support the notion that epigenetic-driven changes in synaptic plasticity operate as the mechanistic substrate of psychedelic’s long-lasting antidepressant action but also warn on the limitations in individuals with underlying risk for psychosis.