小胶质细胞TAK1在小鼠抑郁样行为中的作用机制  

Role of microglial TAK1 in depressive-like behaviour in mice

作　　者：王锐雯 周辰 程子雯 史辉燕 陈寅生 王清秀 WANG Ruiwen;Zhou Chen;CHENG Ziwen;SHI Huiyan;CHEN Yinsheng;WANG Qingxiu(School of Medicine,Tongji University,Shanghai 200092,China;Department of Anesthesiology,Shang East Hospital,School of Medicine,Tongji University,Shanghai 200120,China)

机构地区：[1]同济大学医学院,上海200092 [2]同济大学附属东方医院麻醉科,上海200120

出　　处：《同济大学学报(医学版)》2025年第1期8-14,共7页Journal of Tongji University(Medical Science)

基　　金：上海市浦东新区卫生健康委员会重要薄弱学科项目(PWZbr2022-01);上海市浦东新区峰会(急诊医学与重症监护)建设项目(PWYgf2021-03)。

摘　　要：目的探讨小胶质细胞转化生长因子β活化激酶1(transforming growth factor beta kinase 1,TAK1)在小鼠抑郁样行为中的作用。方法使用Cre/LoxP系统构建小胶质细胞特异性敲除TAK1基因小鼠模型;通过慢性束缚应激建立抑郁模型。将CX3CR1^(cre+/-)、TAK1^(flox/flox)(cKO)小鼠和同窝TAK1^(flox/flox)(f/f)雄性小鼠随机分为对照组(control group,CON组)、慢性束缚模应激组(chronic restraint stress group,CRS组),每组8只。造模21 d后,进行行为学测试。使用RT-qPCR测量海马区IL-1β、IL-6、TNF-α的mRNA水平来评估炎症水平;通过免疫荧光试验观察海马区小胶质细胞的激活情况;通过Western印迹法检测p-ERK1/2、ERK1/2蛋白的表达水平。结果cKO小鼠小胶质细胞中TAK1 mRNA的水平较f/f小鼠明显下降(P<0.001)。CRS组中cKO小鼠与f/f小鼠相比,在旷场中心区域停留的时间明显增加(P<0.01),在悬尾实验和强迫游泳中不动的时间明显减少(均P<0.05);小鼠海马区TNF-α、IL-6 mRNA水平明显减少(P<0.01,P<0.05),IL-1β mRNA水平差异没有统计学意义(P>0.05);小鼠海马区CA1区Iba1阳性细胞数量显著减少(P<0.05);小鼠海马区的ERK1/2磷酸化水平显著升高(P<0.05)。结论小胶质细胞特异性敲除TAK1可有效改善CRS诱导的小鼠抑郁样行为,降低海马区炎症水平,抑制小胶质细胞的激活,这可能是通过促进ERK1/2磷酸化途径来实现的。Objective To investigate the role of microglial transforming growth factor beta kinase 1(TAK1)in depressive-like behavior in mice.Methods Microglia-specific knockout TAK1 mice were constructed by using the Cre/LoxP system.Chronic bound-mode stress was used to establish a depression model,CX3CR1^(cre+/-);TAK1^(flox/flox)(cKO)mice and TAK1^(flox/flox)(f/f)male mice from the same litter were randomly divided into control(CON)group,and chronic restraint stress(CRS)group with 6 mice in each group.Behavioral tests were performed 21 days after modelling.Real-time quantitative polymerase chain reaction(RT-qPCR)was used to measure mRNA levels of IL-6 and TNF-αin the hippocampus to assess inflammation.Activation of microglia in the hippocampus was observed by immunofluorescence.The expression levels of p-ERK1/2 and ERK1/2 proteins were detected by Western blotting.Results The level of TAK1 mRNA in microglia of cKO mice was significantly decreased(P<0.001)when compared with that in f/f mice.cKO mice in the CRS group spent significantly more time in the central area in the open field test(P<0.01)and significantly less time of immobility in the tail suspension test and forced swimming test when compared with those in f/f mice(both P<0.05).In the CRS group,TNF-αand IL-6 mRNA levels in the hippocampal region of the cKO mice were both significantly lower than those of the f/f mice(both P<0.05),while the difference in IL-1βmRNA level was not statistically significant(P>0.05).The number of Iba1-positive cells in cKO mice in the hippocampal region was significantly decreased when compared with that in f/f mice in the CRS group(P<0.05).cKO mice in the CRS group had significantly higher ERK1/2 phosphorylation levels in the hippocampus than those in the f/f mice(P<0.05).Conclusion It's indicated that microglia-specific knockdown of TAK1 effectively ameliorates CRS-induced depressive-like behaviors,reduces inflammation levels in the hippocampal region of mice,and inhibites microglia activation,which may be achieved by promoting ERK1

关 键 词：抑郁 小胶质细胞 神经炎症 海马 TAK1基因 小鼠 

分 类 号：R749.1[医药卫生—神经病学与精神病学]