Involvement of Interleukin-1 in Lipopolysaccaride-Induced Microglial Activation and Learning and Memory Deficits
Involvement of Interleukin-1 in Lipopolysaccaride-Induced Microglial Activation and Learning and Memory Deficits
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DOI：
10.1002/jnr.22582
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Yoshida, T.
中科院分区：
文献类型：
--
作者：
Tanaka, S.;Kondo, H.;Yoshida, T.
我们开发了一种与小鼠大脑中小胶质细胞激活相关的学习和记忆障碍动物模型。将脂多糖注射到小鼠海马的 CA1 区域会导致炎症细胞因子（例如白细胞介素 1 β）的产生增加。 IL-1β 的免疫染色显示脂多糖注射后 6 小时信号增加。 IL-1β 免疫阳性细胞与 CD11b 免疫阳性细胞共定位。当进行亚急性脂多糖治疗（20μg/2μl/注射，双侧连续5天）时，在野生型小鼠中观察到小胶质细胞的长期激活以及使用逐步被动回避测试评估的学习和记忆缺陷。 N-甲基-D-天冬氨酸受体 NR1 和 NR2A 亚基的基因表达也因脂多糖处理而降低。相比之下，在亚急性脂多糖治疗后，缺乏白细胞介素-1α和-1β的小鼠中没有观察到小胶质细胞的激活和相关的行为缺陷，并且NR1和NR2A亚基的基因表达几乎没有变化。然而，亚急性脂多糖治疗对肿瘤坏死因子-α 敲除小鼠的这些参数产生了与野生型动物几乎相似的变化。连续5天注射白细胞介素1β中和抗体与脂多糖可改善脂多糖引起的学习和记忆缺陷。这些发现表明，IL-1 的表达在脂多糖诱导的小胶质细胞激活以及相关的学习和记忆功能缺陷中发挥着重要作用。 (C) 2011 Wiley-Liss, Inc.
We have developed an animal model of learning and memory impairment associated with activation of microglia in the mouse brain. Injection of lipopolysaccharide into the CA1 region of the mouse hippocampus resulted in an increased production of inflammatory cytokines, such as interleukin-1 beta. Immunostaining for interleukin-1 beta revealed an increase in the signal at 6 hr after lipopolysaccharide injection. Immunopositive cells for interleukin-1 beta were colocalized with those immunopositive for CD11b. When subacute lipopolysaccharide treatment (20 mu g/2 mu l/injection, bilaterally for 5 consecutive days) was performed, long-term activation of microglia and learning and memory deficits as evaluated using a step-through passive avoidance test were observed in the wild-type mice. Gene expression of the N-methyl-D-aspartate receptor NR1 and NR2A subunits was also decreased by the lipopolysaccharide treatment. In contrast, activation of microglia and the associated behavioral deficits were not observed in mice lacking interleukin-1 alpha and -1 beta following the subacute lipopolysaccharide treatment, together with little change in the gene expression of NR1 and NR2A subunits. However, the subacute lipopolysaccharide treatment produced almost similar changes in those parameters in the tumor necrosis factor-alpha knockout mice as in the wild-type animals. The injection of interleukin-1 beta neutralizing antibody with lipopolysaccharide for 5 consecutive days resulted in the improvement of lipopolysaccharide-induced learning and memory deficits. These findings suggest that the expression of interleukin-1 plays an important role in lipopolysaccharideinduced activation of microglia and the associated functional deficits in learning and memory. (C) 2011 Wiley-Liss, Inc.