Wang Lu, Ling Hanyi, He Hui, Hu Nan, Xiao Lin, Zhang Yue, Xie Lei, You Zili
The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, 610054, China.
School of Life Science and Technology, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China.
Neurobiol Stress. 2023 Jun 25;25:100553. doi: 10.1016/j.ynstr.2023.100553. eCollection 2023 Jul.
Microglia are involved in sleep/wake cycles and the response to sleep loss. Synaptic pruning by microglia is necessary for central nervous system circuit refinement and contributes to cognitive function. Here, we investigated whether and how microglia-mediated synaptic pruning may be involved in cognitive deficits induced by sleep deprivation in mice. Mice were deprived of sleep by leaving them in a spontaneously rotating rod for 72 h, after which their cognitive function was assessed using an object location test, Y maze, and novel object recognition test. Sleep deprivation lowered the discrimination index for familiar locations in the object location test and Y maze. Microglial morphology was assessed using immunostaining Iba1, while microglia-mediated synaptic pruning was examined based on immunostaining PSD95, CD68, and Iba1. Sleep deprivation also activated microglial cells in the hippocampus, as reflected in bigger soma as well as fewer and shorter branches than normal sleep. Sleep deprivation downregulated phagocytic markers and internalization of postsynaptic protein 95 (PSD95), suggesting impaired synaptic pruning. CX3C motif chemokine receptor 1 (CX3CR1) signaling was detected in experiments. Sleep deprivation also downregulated CX3CR1. Activation of CX3CR1 signaling increased phagocytosis activity of BV2 microglia . Sleep deprivation dysregulates microglial CX3CR1 signaling and inhibits synaptic pruning, contributing to associated cognitive deficits. These findings identify CX3CR1-dependent synaptic pruning as a potential therapeutic target in which sleep deprivation causes recognition impairments.
小胶质细胞参与睡眠/觉醒周期以及对睡眠剥夺的反应。小胶质细胞介导的突触修剪对于中枢神经系统回路的优化是必要的，并有助于认知功能。在此，我们研究了小胶质细胞介导的突触修剪是否以及如何参与小鼠睡眠剥夺诱导的认知缺陷。通过将小鼠置于自动旋转杆上72小时使其睡眠剥夺，之后使用物体位置测试、Y迷宫和新物体识别测试评估它们的认知功能。睡眠剥夺降低了物体位置测试和Y迷宫中对熟悉位置的辨别指数。使用免疫染色Iba1评估小胶质细胞形态，同时基于免疫染色PSD95、CD68和Iba1检查小胶质细胞介导的突触修剪。睡眠剥夺还激活了海马体中的小胶质细胞，表现为与正常睡眠相比，细胞体更大，分支更少且更短。睡眠剥夺下调了吞噬标记物和突触后蛋白95（PSD95）的内化，表明突触修剪受损。在实验中检测到CX3C基序趋化因子受体1（CX3CR1）信号传导。睡眠剥夺还下调了CX3CR1。CX3CR1信号传导的激活增加了BV2小胶质细胞的吞噬活性。睡眠剥夺使小胶质细胞CX3CR1信号传导失调并抑制突触修剪，导致相关的认知缺陷。这些发现确定CX3CR1依赖性突触修剪是睡眠剥夺导致认知障碍的一个潜在治疗靶点。
