Chronic stress in both humans and rodents induces a robust downregulation of neuroligin-2, a key component of the inhibitor)' synapse, in the NAc that modifies behavioral coping mechanisms and stress resiliency in mice. Here we extend this observation by examining the role of two other inhibitor)' synapse constituents, vesicular GABA transporter (vGAT) and gephvrin, in the NAc of male mice that undement chronic social defeat stress (CSDS) and in patients with major depressive disorder (MDD). We first performed transcriptional profiling of vGAT and gephvrin in postmortem NAc samples from a cohort of healthy controls, medicated, and nonmedicated MDD patients. In parallel, we conducted whole-cell electrophysiology recordings in the NAc of stress-susceptible and stress-resilient male mice following 10 d of CSDS. Finally, we used immunohistochemistry to analyze protein levels of vGAT and gephyrin in the NAc of mice after CSDS. We found that decreased vGAT and gephyrin mRNA in the NAc of nonmedicated MDD patients is paralleled by decreased inhibitory synapse markers and decreased frequency of mini inhibitory postsynaptic currents (mIPSC) in the NAc of susceptible mice, indicating a reduction in the number of NAc inhibitor)' synapses that is correlated with depression-like behavior. Overall, these findings suggest a common state ot reduced inhibitor)' tone in the NAc in depression and stress susceptibility. [ABSTRACT FROM AUTHOR]