Depression is one of the most common mental disorders with an increasing incidence. However, factors involved in depression are so complex, thus it is difficult to find effective strategies to reverse the impairments. This study aims to verify the role of regulator of G protein signaling 2 (RGS2) in the mouse mode of unpredictable mild stress-induced depression-like behaviors. Knockdown of RGS2 was achieved by transfection of siRNA-RGS2 in mouse hippocampal (HT-22) cells in vitro and injection of recombinant adenovirus expressing siRNA-RGS2 in mice in vivo. An aberrant high expression of RGS2 was found in mice with depression-like behaviors through immunohistochemical analysis. Silencing of RGS2 or Forskolin (activator of cAMP pathway) developed sweet water consumption, reduced inflammation and oxidative stress injury, and attenuated cognitive impairment and neuronal damage in mice with depression-like behaviors. Furthermore, regeneration was enhanced and apoptosis was repressed in mouse hippocampal neurons in the presence of RGS2 knockdown and Forskolin. Mechanistic studies indicated that silencing of RGS2 promoted the activation of cAMP pathway, thus rescuing depression-like behaviors of mice. Collectively, our study uncovered the role of RGS2-dependent cAMP pathway in regulation of cognitive impairment and hippocampal neuron regeneration in depression-like behaviors of mice, which may be a potential therapeutic target for impairments and symptoms associated with depression.

抑郁症是最常见的精神障碍之一，发病率不断增加。然而，抑郁症涉及的因素如此复杂，因此很难找到有效的策略来扭转这种损害。本研究旨在验证 G 蛋白信号转导 2 (RGS2) 调节剂在不可预测的轻度应激诱导的抑郁样行为的小鼠模式中的作用。敲低RGS2的混合物通过siRNA-RGS2转染小鼠海马实现（HT-22）的细胞在体外和重组腺病毒在小鼠中表达的siRNA-RGS2的注入体内. 通过免疫组织化学分析，在具有抑郁样行为的小鼠中发现了 RGS2 的异常高表达。沉默 RGS2 或 Forskolin（cAMP 通路的激活剂）会消耗甜水，减少炎症和氧化应激损伤，并减轻具有抑郁样行为的小鼠的认知障碍和神经元损伤。此外，在 RGS2 敲低和 Forskolin 存在的情况下，小鼠海马神经元的再生得到增强，细胞凋亡受到抑制。机制研究表明，RGS2 的沉默促进了 cAMP 通路的激活，从而挽救了小鼠的抑郁样行为。总的来说，我们的研究揭示了 RGS2 依赖性 cAMP 通路在调节小鼠抑郁样行为中的认知障碍和海马神经元再生中的作用，