N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

中文翻译：

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慢性社交衰竭应激的易感性与低海马突触外NMDA受体功能有关。

N-甲基-D-天冬氨酸受体（NMDARs）已高度参与抑郁症的发病机理和治疗。尽管在谷氨酸突触的内部和外部都可以发现NMDAR，但尚不清楚突触处（sNMDAR）和突触外位置（exNMDAR）的NMDAR在与抑郁相关的行为形成中是否发挥不同的作用。使用慢性社交挫败压力（CSDS），一种与焦虑和抑郁相关的行为的动物模型，我们发现对CSDS敏感的小鼠表现出低的海马exNMDAR功能。通过增强星形胶质细胞胱氨酸-谷氨酸反转运蛋白释放谷氨酸盐或用不能进入突触间隙的激动剂包被的金纳米颗粒靶向突触外受体来提高exNMDAR功能，可以防止应激小鼠的社交回避行为。有趣的是，氯胺酮 它是一种速效抗抑郁药，对sNMDAR的阻滞作用比对exNMDAR的阻滞作用强。这些发现表明，小鼠对CSDS的敏感性和适应力分别与海马的exNMDAR功能低和高有关。增强exNMDAR功能可能是一种针对情绪和焦虑症的新颖治疗方法。