Systemic histone deacetylase inhibition ameliorates the aberrant responses to acute stress in socially isolated male mice.

Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SI(RS) males. Compared to group-housed counterparts, SI(RS) males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SI(RS) males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SI(RS) male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SI(RS)). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SI(RS) males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.