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

A single dose of the psychedelic DOI produces rapid and sustained antidepressant-like effects by altering chromatin organization at enhancer regions of genes involved in synaptic assembly in the frontal cortex, an effect mediated by the 5-HT2A receptor. These epigenetic changes drive lasting synaptic plasticity and accelerate fear extinction. The findings suggest that epigenetic-driven synaptic plasticity underlies psychedelics' long-lasting antidepressant action, but also indicate potential risks for individuals with underlying vulnerability to psychosis, as the altered neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.

Study at a glance

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.