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

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 ofDOI 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 DOIinduced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomicdriven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.

Automated summary

Clinical evidence shows that rapid and sustained antidepressant effects can be achieved with a single exposure to psychedelics. The study found that a single dose of the psychedelic DOI has fast-acting effects on the frontal cortex dendritic spine structure and accelerates fear extinction through the 5-HT2A receptor. Furthermore, DOI induces changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly, which overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.