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  • Title: Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain.
    Author: Ni RJ, Wang YY, Gao TH, Wang QR, Wei JX, Zhao LS, Ma YR, Ma XH, Li T.
    Journal: Zool Res; 2023 May 18; 44(3):543-555. PubMed ID: 37147908.
    Abstract:
    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 were most significantly associated with the expression of inflammation-related genes ( NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain. N-甲基-D-天门冬氨酸受体（NMDAR）拮抗剂MK-801（地佐环平）的急性给药已用来构建精神疾病的动物模型。然而，小胶质细胞和炎症相关基因在精神疾病中的作用仍然未知。该研究发现，通过饮用水给予集落刺激因子1受体（CSF1R）/c-Kit激酶双重抑制剂PLX3397（培西达替尼）后，小鼠前额叶皮层（PFC）和海马（HPC）中的小胶质细胞被迅速清除。MK-801单次给药诱导小鼠在旷场实验（OFT）中表现高活动行为。重要的是，PLX3397介导的小胶质细胞耗竭阻止了MK-801诱导的高活动行为和精神分裂症样行为。然而，小胶质细胞的再增殖或米诺环素（小胶质细胞激活的抑制剂）治疗都对MK-801诱导的高活动行为没有影响。更重要的是，PFC和HPC中的小胶质细胞密度与这些行为变化显著相关。此外，在PLX3397和/或MK-801处理的小鼠大脑中观察到了相同的和差异的谷氨酸、γ-氨基丁酸和炎症相关的基因表达模式（116个基因）。此外，使用层次聚类分析鉴定了脑中强相关性的10个共同的炎症相关基因（ CD68、 CD163、 CD206、 TMEM119、 CSF3R、 CX3CR1、 TREM2、 CD11b、 CSF1R和 F4/80）。进一步的相关性分析证明，在PLX3397和MK-801处理的小鼠中，OFT的行为变化与这些炎症相关基因表达（ NLRP3、 CD163、 CD206、 F4/80、 TMEM119和 TMEM176a）具有最显著的相关性，但与谷氨酸或γ-氨基丁酸相关基因表达则没有显著相关性。总之，我们的结果表明，CSF1R/c-Kit激酶抑制剂耗竭小胶质细胞可以改善NMDAR拮抗剂诱导的高活动行为，这与大脑中的免疫相关基因的调控相关。.
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