An epigenetic mechanism of social isolation stress in adolescent female mice

Social isolation during adolescence can increase the risk of mental disorders. Epigenetic changes induced by chronic social isolation may serve as a mechanism underlying emotional disturbances. To test this, we exposed female mice to a post-weaning 6-week social isolation (SI) stress. We found the significantly increased methylation of histone H3 at lysine 9 (H3K9), a histone mark linked to gene repression, as well as the increased H3K9 methyltransferases SUV39H1 and SETDB1, in prefrontal cortex (PFC) of SI females. To find out potential downstream genes affected by this epigenetic alteration, we examined genes linked to neuronal and synaptic functions. Activity-dependent genes, including Arc, c-Fos and Npas4, were significantly reduced in PFC of SI females, correlated with the increased H3K9me2 occupancy around Arc enhancer. Treatment of SI females with UNC0642, a selective inhibitor of H3K9 methylation, significantly attenuated the anxiety-like behavior and elevated Arc expression. These results have revealed an epigenetic mechanism and intervention avenue for anxiety induced by chronic social isolation.