Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure.

Abstract

Adolescent binge drinking is a major risk factor for psychiatric disorders later in life including alcohol use disorder. Adolescent alcohol exposure induces epigenetic reprogramming at the enhancer region of the activity-regulated cytoskeleton-associated protein (Arc) immediate-early gene, known as synaptic activity response element (SARE), and decreases <i>Arc</i> expression in the amygdala of both rodents and humans. The causal role of amygdalar epigenomic regulation at <i>Arc</i> SARE in adult anxiety and drinking after adolescent alcohol exposure is unknown. Here, we show that dCas9-P300 increases histone acetylation at the <i>Arc</i> SARE and normalizes deficits in <i>Arc</i> expression, leading to attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. Conversely, dCas9-KRAB increases repressive histone methylation at the <i>Arc</i> SARE, decreases <i>Arc</i> expression, and produces anxiety and alcohol drinking in control rats. These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.