MicroRNA-137 Drives Epigenetic Reprogramming in he Adult Amygdala and Behavioral Changes after Adolescent Alcohol Exposure

Adolescent binge drinking is a serious public health concern and a risk factor for alcohol use disorder (AUD) and comorbid anxiety in adulthood. Chromatin remodeling mediated by epigenetic enzymes including lysine-specific demethylase 1 (LSD1) due to adolescent alcohol exposure may play a role in adult psychopathology. The mechanism by which adolescent alcohol exposure mechanistically regulates epigenetic reprogramming and behavioral changes in adulthood is unknown. We investigated the role of microRNA-137 (miR-137), which is crucial for normal neurodevelopment and targets LSD1, in adolescent intermittent ethanol (AIE) exposure-induced anxiety-like and alcohol-drinking behaviors and related epigenetic reprogramming in the amygdala in adulthood. Adolescent rats were exposed to 2 g/kg ethanol (2 d on/off; AIE) or adolescent intermittent saline (AIS) during postnatal days (PND)28-PND41 and allowed to grow to adulthood for analysis of behavior, miRNA expression, and epigenetic measures in the amygdala. Interestingly, miR-137 was increased and its target genes Lsd1 and Lsd1 + 8a were decreased in the AIE adult amygdala. Infusion of miR-137 antagomir directly into the central nucleus of the amygdala (CeA) rescues AIE-induced alcohol-drinking and anxiety-like behaviors via normalization of decreased Lsd1 expression, decreased LSD1 occupancy, and decreased Bdnf IV expression due to increased H3K9 dimethylation in AIE adult rats. Further, concomitant Lsd1 small interfering RNA (siRNA) infusion into the CeA prevents the miR-137-mediated reversal of AIE-induced adult anxiety and chromatin remodeling at the Bdnf IV promoter. These novel results highlight miR-137 as a potential therapeutic target for anxiety and AUD susceptibility after adolescent alcohol exposure in adulthood.