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

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

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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.

MicrogliaPsychiatric disordersPrefrontal cortexHippocampusImmunityColony-stimulating factor 1 receptor

Rong-Jun Ni、Yi-Yan Wang、Tian-Hao Gao、Qi-Run Wang、Jin-Xue Wei、Lian-Sheng Zhao、Yang-Rui Ma、Xiao-Hong Ma、Tao Li

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Mental Health Center and Psychiatric Laboratory,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China

Sichuan Clinical Medical Research Center for Mental Disorders,Chengdu,Sichuan 610044,China

Golden Apple Jincheng NO.1 Secondary School,Chengdu,Sichuan 610213,China

Affiliated Mental Health Center & Hangzhou Seventh People's Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310013,China

NHC and CAMS Key Laboratory of Medical Neurobiology,MOE Frontier Science Center for Brain Science and Brain-machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou,Zhejiang 310014,China

Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence,Guangzhou,Guangdong 510799,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaMinistry of Science and Technology of the People's Republic of ChinaMinistry of Science and Technology of the People's Republic of ChinaNatural Science Foundation of Sichuan ProvinceKey Research and Development Program of Science and Technology Department of Sichuan ProvinceKey Research and Development Program of Science and Technology Department of Sichuan ProvinceKey R & D Program of ZhejiangSpecial Foundation for Brain Research from Science and Technology Program of GuangdongChina Postdoctoral Science FoundationChina Postdoctoral Science FoundationSichuan University

8192010801882230046820014322022ZD02117002022ZD02052002022NSFSC160722ZDYF153122ZDYF16962022C030962018B0303340012020TQ02132020M6833192022SCUH0023

2023

10.24272/j.issn.2095-8137.2022.389

动物学研究
中国科学院昆明动物研究所 中国动物学会

动物学研究

CSTPCDCSCD
影响因子：0.582
ISSN：0254-5853
年,卷(期)：2023.44(3)
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