Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain

作者：Rong‐Jun Ni, 四川大学华西医院精神卫生中心和精神医学研究室, 四川 成都 610041, 中国, Yiyan Wang, Tianhao Gao, Qirun Wang, Jinxue Wei, Liansheng Zhao, Yang-Rui Ma, Xiaohong Ma, Tao Li, 四川省精神心理疾病临床医学研究中心, 四川 成都 610044, 中国, 金苹果锦城第一中学, 四川 成都, 中国, 浙江大学医学院附属精神卫生中心, 杭州市第七人民医院, 浙江 杭州310013, 中国, 浙江大学脑科学与脑医学学院NHC和CAMS医学神经生物学重点实验室, 教育部脑与脑机融合前沿科学中心, 浙江 杭州 310014, 中国, 粤港澳大湾区脑科学与类脑研究中心, 广东 广州 510799, 中国 · 发表于：动物学研究 · 年份：2023 · DOI：10.24272/j.issn.2095-8137.2022.389 · 被引用次数：15 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Tryptophan and brain disorders、Stress Responses and Cortisol

Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes ( CD68 , CD163 , CD206 , TMEM119 , CSF3R , CX3CR1 , TREM2 , CD11b , CSF1R , and F4/80 ) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT we...