Volume 44 Issue 3
May  2023
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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. Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain. Zoological Research, 2023, 44(3): 543-555. doi: 10.24272/j.issn.2095-8137.2022.389
Citation: 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. Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain. Zoological Research, 2023, 44(3): 543-555. doi: 10.24272/j.issn.2095-8137.2022.389

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

doi: 10.24272/j.issn.2095-8137.2022.389
Supplementary data to this article can be found online.
The authors declare that they have no competing interests.
R.J.N. and Y.Y.W. were involved in experimental treatments of the animals, acquisition of data, interpretation of data, and writing of the manuscript. T.H.G. was involved in experimental treatments of the animals and tissue processing. Q.R.W. and Y.R.M. were involved in experimental treatments of the animals and histochemical analysis. J.X.W. and L.S.Z. were responsible for revising the manuscript. X.H.M. and T.L. were responsible for experimental design and revising the manuscript. All authors read and approved the final version of the manuscript.
#Authors contributed equally to this work
Funds:  This work was supported by the National Natural Science Foundation of China (81920108018, 82230046, 82001432), Ministry of Science and Technology of the People’s Republic of China (2022ZD0211700, 2022ZD0205200), Natural Science Foundation of Sichuan Province (2022NSFSC1607), Key Research and Development Program of Science and Technology Department of Sichuan Province (22ZDYF1531, 22ZDYF1696), Key R & D Program of Zhejiang (2022C03096), Special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001), China Postdoctoral Science Foundation (2020TQ0213, 2020M683319), and Sichuan University (2022SCUH0023)
More Information
  • 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.
  • Supplementary data to this article can be found online.
    The authors declare that they have no competing interests.
    R.J.N. and Y.Y.W. were involved in experimental treatments of the animals, acquisition of data, interpretation of data, and writing of the manuscript. T.H.G. was involved in experimental treatments of the animals and tissue processing. Q.R.W. and Y.R.M. were involved in experimental treatments of the animals and histochemical analysis. J.X.W. and L.S.Z. were responsible for revising the manuscript. X.H.M. and T.L. were responsible for experimental design and revising the manuscript. All authors read and approved the final version of the manuscript.
    #Authors contributed equally to this work
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