Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, QC, Canada.
Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada.
Neuropsychopharmacology. 2019 Jun;44(7):1310-1318. doi: 10.1038/s41386-019-0325-8. Epub 2019 Jan 25.
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.
N-甲基-D-天冬氨酸受体（NMDARs）在抑郁症的发病机制和治疗中起着至关重要的作用。尽管 NMDAR 可以存在于谷氨酸突触内外，但突触（sNMDAR）和突触外（exNMDAR）位置的 NMDAR 对抑郁相关行为的形成是否发挥不同作用仍不清楚。我们利用慢性社交挫败应激（CSDS）这一焦虑和抑郁相关行为的动物模型发现，易患 CSDS 的小鼠表现出海马体 exNMDAR 功能低下。通过增强星形胶质细胞胱氨酸-谷氨酸反向转运体释放谷氨酸，或用不能进入突触间隙的配体包被金纳米颗粒靶向突触外受体，提高 exNMDAR 功能，可以预防应激小鼠的社交回避行为。有趣的是，作为一种快速起效的抗抑郁药，氯胺酮对 sNMDAR 的阻断作用强于 exNMDAR。这些发现表明，小鼠对 CSDS 的易感性和抵抗力分别与海马体中低 exNMDAR 和高 exNMDAR 功能有关。增强 exNMDAR 功能可能成为治疗情绪和焦虑障碍的新方法。
