de la Fuente Revenga, MarioZhu, BohanGuevara, Christopher A.Naler, Lynette B.Saunders, Justin M.Zhou, ZiruiToneatti, RudySierra, SalvadorWolstenholme, Jennifer T.Beardsley, Patrick M.Huntley, George W.Lu, ChangGonzález-Maso, Javier2021-11-192021-11-192021-10-19http://hdl.handle.net/10919/106684Clinical 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.application/pdfenCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalArticle - Refereedhttps://doi.org/10.1016/j.celrep.2021.10983637