Prolonged epigenomic 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
Affiliations
Mario de la Fuente Revenga
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA
Bohan Zhu
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA 24061, USA
Christopher A. Guevara
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Lynette B. Naler
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA 24061, USA
Justin M. Saunders
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Zirui Zhou
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA 24061, USA
Rudy Toneatti
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Salvador Sierra
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Jennifer T. Wolstenholme
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Patrick M. Beardsley
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
George W. Huntley
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Chang Lu
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA 24061, USA; Corresponding author
Javier González-Maeso
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Corresponding author
Summary: 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.
