Dysfunction in glutamate homeostasis contributes to the pathology of depression-like behavior. Using a chronic restraint stress (CRS) model of depression in C57BL/6 mice, we measured glutamate levels in the cerebrospinal fluid at different restraint time points (CRS 1 d, CRS 3 d, CRS 5 d, CRS 7 d, CRS 14 d, and CRS 21 d). Glutamate levels were increased in the early stage of stress (CRS 1 d and CRS 5 d) but returned to basal levels at the other time points (CRS 7 d-21 d). We hypothesized that glutamate-induced excitotoxicity is critical for the development of depression-like behavior in the CRS model. Treatment with sodium valproate (VPA) or lamotrigine (LTG), two drugs that prevent excitotoxicity in neurons by increasing inhibitory inputs or blocking sodium channels, in the early stage (CRS 1 d-5 d) was sufficient to correct depression-like behavior. In contrast, treatment with the classic antidepressant fluoxetine (FLX) during the same time period was not sufficient to correct depressive behavior. Western blot of two markers of dendritic spines PSD95 and VGluT1 showed that restraining mice for 5 d resulted in the loss of dendritic spines, which was rescued by VPA or LTG. In conclusion, an initial increase in glutamate levels plays an important role in the development of depression-like behavior in the CRS model.

谷氨酸稳态功能障碍导致抑郁样行为的病理学。使用 C57BL/6 小鼠抑郁症的慢性束缚应激 (CRS) 模型，我们测量了不同束缚时间点（CRS 1 天、CRS 3 天、CRS 5 天、CRS 7 天、CRS 14 天）脑脊液中的谷氨酸水平和通用报告准则第 21 条 d)。谷氨酸水平在压力的早期阶段（CRS 1 d 和 CRS 5 d）增加，但在其他时间点（CRS 7 d-21 d）恢复到基础水平。我们假设谷氨酸诱导的兴奋性毒性对于 CRS 模型中抑郁样行为的发展至关重要。用丙戊酸钠 (VPA) 或拉莫三嗪 (LTG) 治疗，这两种药物可通过增加抑制输入或阻断钠通道来防止神经元兴奋性毒性，在早期阶段（CRS 1 d-5 d）足以纠正抑郁样行为。相比之下，在同一时间段内使用经典抗抑郁药氟西汀 (FLX) 治疗不足以纠正抑郁行为。对树突棘PSD95和VGluT1这两个标志物进行Western印迹显示，将小鼠禁锢5 d导致树突棘丢失，VPA或LTG将其挽救。总之，谷氨酸水平的初始增加在 CRS 模型中抑郁样行为的发展中起着重要作用。被VPA或LTG救出。总之，谷氨酸水平的初始增加在 CRS 模型中抑郁样行为的发展中起着重要作用。被VPA或LTG救出。总之，谷氨酸水平的初始增加在 CRS 模型中抑郁样行为的发展中起着重要作用。