Low-Input Technology Reveals Prolonged Epigenomic Alterations Following Single Exposure to a Psychedelic in Mice

Clinical evidence suggests a strong therapeutic effect of 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. Epigenetic mechanisms such as histone modifications play critical roles in adaptive tuning of chromatin structures and gene expression. Here, we use a low-input genome-wide profiling technology (MOWChIP-seq, microfluidic oscillatory washing-based chromatin immunoprecipitation followed by sequencing) to investigate the effect of a single dose of a psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) in mice brains. Our low-input technologies allowed us to profile both epigenomic and transcriptomic dynamics in neurons from prefrontal cortex after DOI exposure. We discovered changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure. In comparison, transcriptomic changes were much more short-lived and transient. 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.