Disinhibition of somatostatin interneurons confers resilience to stress in male but not female mice

Chronic stress represents a vulnerability factor for anxiety and depressive disorders and has been widely used to model aspects of these disorders in rodents. Disinhibition of somatostatin (SST)-positive GABAergic interneurons in mice by deletion of γ2 GABA(A) receptors selectively from these cells (SSTCre:γ2(f/f) mice) has been shown to result in behavioral and biochemical changes that mimic the responses to antidepressant doses of ketamine. Here we explored the extent to which SSTCre:γ2(f/f) mice exhibit resilience to unpredictable chronic mild stress (UCMS). We found that male SSTCre:γ2(f/f) mice are resilient to UCMS-induced (i) reductions in weight gain, (ii) reductions in SST-immuno-positive cells in medial prefrontal cortex (mPFC), (iii) increases in phosphorylation of eukaryotic elongation factor 2 (eEF2) in mPFC, and (iv) increased anxiety in a novelty suppressed feeding test. Female SSTCre:γ2(f/f) mice were resilient to UCMS-induced reductions in SST-immuno-positive cells indistinguishably from males. However, in contrast to males, they showed no UCMS effects on weight gain independent of genotype. Moreover, in mPFC of female γ2(f/f) control mice, UCMS resulted in paradoxically reduced p-EF2 levels without stress effects in the SSTCre:γ2(f/f) mutants. Lastly, female SSTCre:γ2(f/f) mice showed increased rather than reduced UCMS induced anxiety compared to γ2(f/f) controls. Thus, disinhibition of SST interneurons results in behavioral resilience to UCMS selectively in male mice, along with cellular resilience of SST neurons to UCMS independent of sex. Thus, mechanisms underlying vulnerability and resilience to stress are sex specific and map to mPFC rather than hippocampus but appear unrelated to changes in expression of SST as a marker of corresponding interneurons.