Department of Biochemical Toxicology, School of Pharmacy, Showa University, Tokyo, Japan.
J Neurosci Res. 2011 Apr;89(4):506-14. doi: 10.1002/jnr.22582. Epub 2011 Feb 2.
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-1β. Immunostaining for interleukin-1β revealed an increase in the signal at 6 hr after lipopolysaccharide injection. Immunopositive cells for interleukin-1β were colocalized with those immunopositive for CD11b. When subacute lipopolysaccharide treatment (20 μg/2 μl/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-1α and -1β 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-α knockout mice as in the wild-type animals. The injection of interleukin-1β 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 lipopolysaccharide-induced activation of microglia and the associated functional deficits in learning and memory.
我们已经建立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的动物模型。向小鼠海马 CA1 区注射脂多糖会导致炎症细胞因子（如白细胞介素-1β）的产生增加。白细胞介素-1β的免疫染色显示，脂多糖注射后 6 小时信号增加。白细胞介素-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处理（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穿梭式被动回避测试评估的学习和记忆缺陷。脂多糖处理还降低了 N-甲基-D-天冬氨酸受体 NR1 和 NR2A 亚基的基因表达。相比之下，在亚急性脂多糖处理后，缺乏白细胞介素-1α 和 -1β 的小鼠中未观察到小胶质细胞的激活及其相关的行为缺陷，NR1 和 NR2A 亚基的基因表达也几乎没有变化。然而，亚急性脂多糖处理在肿瘤坏死因子-α 敲除小鼠中产生了与野生型动物几乎相似的参数变化。在连续 5 天注射脂多糖的同时注射白细胞介素-1β 中和抗体可改善脂多糖诱导的学习和记忆缺陷。这些发现表明白细胞介素-1 的表达在脂多糖诱导的小胶质细胞激活及其在学习和记忆中的相关功能缺陷中起着重要作用。
