A pivotal role of glutamatergic neurotransmission in the pathophysiology of major depressive disorder (MDD) has been supported in preclinical and clinical studies. Glutamate transporters are responsible for rapid uptake of glutamate to maintain glutamate homeostasis. Down-regulation of glutamate transporters has been reported in MDD patients and animal models. However, the mechanism for stress-induced modulation of glutamate transporter expression is poorly understood. Receptor for advanced glycosylation end products (RAGE), a member of immunoglobulin family, is found expressed widely in brain and play important roles in neuronal development, neurite growth, neurogenesis and neuroinflammation. Our study showed chronic unpredictable stress (CUS) induced depressive-like behaviors and reduced RAGE expression in hippocampus DG, CA1 and CA3 areas. The protein levels of GLT-1, p-CREB and p-p65 decreased in hippocampus DG as well. Knockdown of RAGE expression in hippocampus DG with RAGE shRNA lentivirus particles induced depressive-like behaviors. Meanwhile, the protein and mRNA levels of GLT-1 were significantly decreased as well as phosphorylation of CREB and p65. Neither CUS nor RAGE knockdown altered GLAST protein and mRNA levels. These findings suggested that RAGE/CREB-NF-κB signaling pathway in hippocampus DG involved in modulation of GLT-1 expression, which possibly contributed to the depressive-like behavior induced by CUS.

谷氨酸能神经传递在重度抑郁症 (MDD) 病理生理学中的关键作用已得到临床前和临床研究的支持。谷氨酸转运蛋白负责快速摄取谷氨酸以维持谷氨酸稳态。据报道，MDD 患者和动物模型中谷氨酸转运蛋白的下调。然而，对谷氨酸转运蛋白表达的应激诱导调节机制知之甚少。高级糖基化终产物受体 (RAGE) 是免疫球蛋白家族的成员，在大脑中广泛表达，在神经元发育、神经突生长、神经发生和神经炎症中发挥重要作用。我们的研究表明，慢性不可预测压力 (CUS) 会诱导抑郁样行为，并降低海马 DG、CA1 和 CA3 区域的 RAGE 表达。海马 DG 中 GLT-1、p-CREB ​​和 p-p65 的蛋白质水平也降低。用 RAGE shRNA 慢病毒颗粒抑制海马 DG 中的 RAGE 表达可诱导抑郁样行为。同时，GLT-1的蛋白质和mRNA水平以及CREB和p65的磷酸化显着降低。CUS 和 RAGE 敲低都不会改变 GLAST 蛋白和 mRNA 水平。这些发现表明，海马 DG 中的 RAGE/CREB-NF-κB 信号通路参与了 GLT-1 表达的调节，这可能与 CUS 诱导的抑郁样行为有关。GLT-1 的蛋白质和 mRNA 水平以及 CREB ​​和 p65 的磷酸化显着降低。CUS 和 RAGE 敲低都不会改变 GLAST 蛋白和 mRNA 水平。这些发现表明，海马 DG 中的 RAGE/CREB-NF-κB 信号通路参与了 GLT-1 表达的调节，这可能与 CUS 诱导的抑郁样行为有关。GLT-1 的蛋白质和 mRNA 水平以及 CREB ​​和 p65 的磷酸化显着降低。CUS 和 RAGE 敲低都不会改变 GLAST 蛋白和 mRNA 水平。这些发现表明，海马 DG 中的 RAGE/CREB-NF-κB 信号通路参与了 GLT-1 表达的调节，这可能与 CUS 诱导的抑郁样行为有关。