Depression and Social Defeat Stress Are Associated with Inhibitory Synaptic Changes in the Nucleus Accumbens
Depression and Social Defeat Stress Are Associated with Inhibitory Synaptic Changes in the Nucleus Accumbens
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DOI：
10.1523/jneurosci.2568-19.2020
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发表时间：
2020-08-05
影响因子：
5.3
通讯作者：
Russo, Scott J.
中科院分区：
文献类型：
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作者：
Heshmati, Mitra;Christoffel, Daniel J.;Russo, Scott J.
人类和啮齿类动物的慢性应激均诱导神经胶质素-2的强烈下调，神经胶质素-2是抑制突触的关键成分，在NAc中改变小鼠的行为应对机制和应激弹性。在这里，我们通过研究另外两种抑制性突触成分，泡状GABA转运蛋白（vGAT）和gephyrin在经历慢性社会失败应激（CSDS）的雄性小鼠和重度抑郁症（MDD）患者的NAc中的作用来扩展这一观察结果。我们首先对来自健康对照、服药和未服药的MDD患者的死后NAc样本进行了vGAT和gephyrin的转录分析。同时，我们在CSDS 10d后对应激易感和应激恢复雄性小鼠的NAc进行了全细胞电生理记录。最后，我们用免疫组织化学方法分析了CSDS后小鼠NAc中vGAT和gephyrin的蛋白水平。我们发现，未服药的MDD患者NAc中vGAT和gephyrin mRNA的降低与易感小鼠NAc中抑制突触标记物的减少和迷你抑制性突触后电流（mIPSC）频率的降低是平行的，表明NAc抑制突触数量的减少与抑郁样行为相关。总的来说，这些发现表明在抑郁和应激易感性中NAc抑制张力降低的共同状态。
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 10d 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.