Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice
Beardsley, P. M., de la Fuente Revenga, M., González-Maeso, J., Guevara, C. A., Huntley, G. W., Lu, C., Naler, L. B., Saunders, J. M., Sierra, S., Toneatti, R., Wolstenholme, J. T., Zhou, Z., Zhu, B.
This rodent study investigated the biological substrates of the enduring effects of the psychedelic DOI on the frontal cortex. It finds that a single dose produced rapid structural changes in dendritic spines and sustained alterations in chromatin organisation related to synaptic plasticity, potentially explaining long-lasting antidepressant actions.
Abstract
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.