Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition

Chronic social defeat stress in mice significantly decreases subsequent social interactions and induces other depression-like behaviors. Here we measured and manipulated levels of acetylated histone H3 (acH3), a chromatin mark of transcriptional activation, in the hippocampus and amygdala after ten continuous days of social defeat stress in male C57/Bl6J mice. This form of social stress causes a transient increase, followed by a persistent decrease, in the levels of acH3 in hippocampus. By comparison, increased acH3 in amygdala was more robust but also highly transient. The persistent decrease in acH3 in hippocampus may be pathological, since it is reversed by chronic fluoxetine administration. Consistent with this hypothesis, infusion of a histone deacetylase (HDAC) inhibitor MS-275 (100 μM) into hippocampus reverses a defeat-induced deficit in sucrose preference, although it does not restore social interaction behavior. Next, different forms of social enrichment were examined with or without hippocampal infusion of MS-275. After social stress, simple pair-housing with another male C57, or female C57, mouse does not reverse social avoidance. However, when HDAC inhibitors are infused into hippocampus during social housing with another male, social avoidance is attenuated. Interestingly, social avoidance is reversed when MS-275 is infused directly into amygdala. Together, these findings further support the antidepressant potential of HDAC inhibitors, and indicate that temporally overlapping environmental and molecular events are required to optimally reverse specific stress-induced behavioral symptoms.

Research highlights
► Repeated stress causes a persistent decrease in acH3K14 in hippocampus.
► Stress-induced deficits in acH3 in hippocampus are reversed by chronic fluoxetine.
► HDAC inhibitor into hippocampus does not reverse stress-induced social avoidance.
► Social “enrichment” after social stress also does not reverse social avoidance.
► Hippocampal HDAC inhibitor paired with social housing attenuates social avoidance.