目的 观察产后早期免疫激活(EPIA)对雌雄小鼠社会行为的影响,探讨星状胶质细胞和小胶质细胞功能状态在此过程中的可能作用。方法 以脂多糖(LPS)诱导的40只EPIA小鼠作为研究对象,分为雄性对照组、雄性模型组、雌性对照组、雌性模型组各10例。各组小鼠于25~32日龄进行行为学检测,利用旷场、三箱社交、埋珠实验检测各组小鼠社会行为能力;采用蛋白免疫印迹法检测大脑皮质和海马组织GFAP、IBA-1、TLR4、NFκB p65蛋白表达水平。结果 行为学检测中,LPS处理显著降低社交指数(F=14.907,P＜0.05)。处理和性别的交互作用在中央区停留时间、埋珠数量上显著(F=5.260、7.788,P＜0.05)。雄性LPS处理减少中央区停留时间、升高埋珠数量(F=4.261、20.645,P＜0.05)。蛋白免疫印迹结果显示LPS处理升高GFAP蛋白在海马和皮质的表达量(F=50.443、30.116,P＜0.05),升高IBA-1蛋白和TLR4蛋白在皮质的表达量(F=21.844、6.215,P＜0.05)。NFκB p65结果显示处理和性别的交互作用在皮质显著(F=6.558,P＜0.05),雌性LPS处理升高皮质NFκB p65蛋白表达量(F= 16.317,P＜0.05)。结论 EPIA足以在小鼠中产生性别特异性孤独症样行为并增强星状胶质细胞和小胶质细胞反应性。EPIA诱导孤独症样行为可能与皮质区TLR4/NFκB信号通路相关。
Abstract
Objective To observe the effects of early postnatal immune activation (EPIA) on social behaviors of male and female mice, and to explore the possible role of the functional state of astrocytes and microglia in this process. Methods Using lipopolysaccharide (LPS) induced EPIA mice as study subjects, mice were divided into the male-control, male-model, female-control, and female-model groups, each containing 10 mice (n=10). Behavioral tests were performed at 25 - 32 days of age, and the social behavior ability of mice was evaluated by open field test, three-chamber sociability test, and marble burying test. The expression levels of GFAP, IBA-1, TLR4, and NFκB p65 in the cortex and hippocampus were detected by Western blot (n=3). Results In behavioral tests, social index significantly decreased in LPS treatment group (F=14.907, P＜0.05). The interaction effect between treatment and sex was significant in the residence time (F =5.260, P<0.05) and the number of buried marbles (F=7.788, P<0.05). LPS treatment decreased the retention time of the central region in male mice (F=4.261, P<0.05), and increased the number of buried marbles in males (F=20.645, P<0.05). Western blot results showed that LPS treatment increased the expression of GFAP protein in the hippocampus (F=50.443, P<0.05) and cortex (F=30.116, P<0.05), as well as the expression of IBA-1 protein (F=21.844. P<0.05) and TLR4 protein (F=6.215, P<0.05) in the cortex. The results of NFκB p65 showed a significant interaction between treatment and sex in the cortex (F=6.558, P<0.05), and LPS increased the expression of NFκB p65 protein in the cortex in female mice (F=16.317, P<0.05). Conclusions EPIA is sufficient to induce sex-specific autism spectrum disorder (ASD)-like behavior and enhance astroglial and microglial reactivity in mice. ASD-like behavior induced by EPIA may be related to the TLR4/NFκB signaling pathway in the cortex.
关键词
孤独症谱系障碍 /
免疫激活 /
脂多糖 /
新生小鼠 /
胶质细胞
Key words
autism spectrum disorder /
immune activation /
lipopolysaccharide /
neonatal mouse /
glial cells
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基金
新疆维吾尔自治区资源共享平台建设项目(PT2215)
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