Nash Family Department of Neuroscience, Friedman Brain Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Douglas Research Centre, McGill University, Montreal, Quebec H4H 1R3, Canada.
J Neurosci. 2020 Aug 5;40(32):6228-6233. doi: 10.1523/JNEUROSCI.2568-19.2020. Epub 2020 Jun 19.
Chronic stress in both humans and rodents induces a robust downregulation of neuroligin-2, a key component of the inhibitory 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 inhibitory synapse constituents, vesicular GABA transporter (vGAT) and gephyrin, in the NAc of male mice that underwent chronic social defeat stress (CSDS) and in patients with major depressive disorder (MDD). We first performed transcriptional profiling of vGAT and gephyrin 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 inhibitory synapses that is correlated with depression-like behavior. Overall, these findings suggest a common state of reduced inhibitory tone in the NAc in depression and stress susceptibility. Existing studies focus on excitatory synaptic changes after social stress, although little is known about stress-induced inhibitory synaptic plasticity and its relevance for neuropsychiatric disease. These results extend our previous findings on the critical role of impaired inhibitory tone in the NAc following stress and provide new neuropathological evidence for reduced levels of inhibitory synaptic markers in human NAc from nonmedicated major depressive disorder patients. This finding is corroborated in stress-susceptible male mice that have undergone chronic social defeat stress, a mouse model of depression, at both the level of synaptic function and protein expression. These data support the hypothesis that reduced inhibitory synaptic transmission within the NAc plays a critical role in the stress response.
慢性应激会导致人和啮齿动物的 NAc 中神经黏附素-2（抑制性突触的关键成分）的表达显著下调，从而改变行为应对机制和小鼠的应激弹性。在这里，我们通过检查 NAc 中另外两种抑制性突触成分囊泡 GABA 转运体（vGAT）和网格蛋白的作用，扩展了这一观察结果，这些成分在经历慢性社交挫败应激（CSDS）的雄性小鼠和患有重度抑郁症（MDD）的患者中发挥作用。我们首先对来自健康对照组、接受药物治疗和未接受药物治疗的 MDD 患者死后 NAc 样本中的 vGAT 和网格蛋白进行了转录谱分析。同时，我们在 CSDS 后 10 天对易感和抗应激雄性小鼠的 NAc 进行全细胞膜片钳电生理记录。最后，我们使用免疫组织化学分析 CSDS 后 NAc 中 vGAT 和网格蛋白的蛋白水平。我们发现，未接受药物治疗的 MDD 患者的 NAc 中 vGAT 和网格蛋白 mRNA 减少，与易感小鼠的 NAc 中抑制性突触标志物减少和迷你抑制性突触后电流（mIPSC）频率降低相平行，这表明 NAc 抑制性突触的数量减少，这与抑郁样行为有关。总的来说，这些发现表明抑郁和应激易感性中 NAc 的抑制性张力普遍降低。现有研究主要集中在社交应激后兴奋性突触的变化，尽管对应激诱导的抑制性突触可塑性及其与神经精神疾病的相关性知之甚少。这些结果扩展了我们之前关于应激后 NAc 中抑制性音调受损的关键作用的发现，并为非药物治疗的重度抑郁症患者的 NAc 中抑制性突触标志物水平降低提供了新的神经病理学证据。这一发现在经历慢性社交挫败应激（一种抑郁的小鼠模型）的易感雄性小鼠中得到了证实，在突触功能和蛋白表达水平上均得到了证实。这些数据支持了这样一种假设，即 NAc 内抑制性突触传递的减少在应激反应中起着关键作用。
