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

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

doi:10.24272/j.issn.2095-8137.2022.389

Volume 44 Issue 3

May 2023

Turn off MathJax

Article Contents

Article Navigation > Zoological Research > 2023 > 44(3): 543-555

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

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

PDF( 9242 KB)

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

Rong-Jun Ni^{1, 2, #},
Yi-Yan Wang^{1, 2, #},
Tian-Hao Gao^{1, 2},
Qi-Run Wang^{1, 2},
Jin-Xue Wei^{1, 2},
Lian-Sheng Zhao^{1, 2},
Yang-Rui Ma³,
Xiao-Hong Ma^{1, 2
,
,},
Tao Li^{4, 5, 6
,
,}

1.
Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
2.
Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan 610044, China
3.
Golden Apple Jincheng NO.1 Secondary School, Chengdu, Sichuan 610213, China
4.
Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China
5.
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
6.
Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong 510799, China

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

Corresponding author: E-mail: maxiaohong@scu.edu.cn; litaozjusc@zju.edu.cn
Received Date: 2022-12-18
Accepted Date: 2023-04-28

Published Online: 2023-05-04

Publish Date: 2023-05-18

Abstract

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.
- Microglia,
- Psychiatric disorders,
- Prefrontal cortex,
- Hippocampus,
- Immunity,
- Colony-stimulating factor 1 receptor

FullText(HTML)

References(39)

References

[1]	Bradford AM, Savage KM, Jones DNC, Kalinichev M. 2010. Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. Psychopharmacology, 212(2): 155−170. doi: 10.1007/s00213-010-1938-0
[2]	Chen PA, Wang HY, Sun CL, Chen ML, Chen YC. 2022. Neurobehavioral differences of valproate and risperidone on MK-801 inducing acute hyperlocomotion in mice. Behavioural Neurology, 2022: 1048463.
[3]	Choudhry P. 2016. High-throughput method for automated colony and cell counting by digital image analysis based on edge detection. PLoS One, 11(2): e0148469. doi: 10.1371/journal.pone.0148469
[4]	Coggeshall RE, Lekan HA. 1996. Methods for determining numbers of cells and synapses: a case for more uniform standards of review. The Journal of Comparative Neurology, 364(1): 6−15. doi: 10.1002/(SICI)1096-9861(19960101)364:1<6::AID-CNE2>3.0.CO;2-9
[5]	Coleman LG Jr, Zou J, Crews FT. 2020. Microglial depletion and repopulation in brain slice culture normalizes sensitized proinflammatory signaling. Journal of Neuroinflammation, 17(1): 27. doi: 10.1186/s12974-019-1678-y
[6]	Elmore MRP, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. 2014. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron, 82(2): 380−397. doi: 10.1016/j.neuron.2014.02.040
[7]	Fagan SC, Edwards DJ, Borlongan CV, Xu L, Arora A, Feuerstein G, et al. 2004. Optimal delivery of minocycline to the brain: implication for human studies of acute neuroprotection. Experimental Neurology, 186(2): 248−251. doi: 10.1016/j.expneurol.2003.12.006
[8]	Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330(6005): 841−845. doi: 10.1126/science.1194637
[9]	Gober R, Ardalan M, Shiadeh SMJ, Duque L, Garamszegi SP, Ascona M, et al. 2022. Microglia activation in postmortem brains with schizophrenia demonstrates distinct morphological changes between brain regions. Brain Pathology, 32(1): e13003.
[10]	Grishagin IV. 2015. Automatic cell counting with ImageJ. Analytical Biochemistry, 473: 63−65. doi: 10.1016/j.ab.2014.12.007
[11]	Hashimoto K. 2022. Gut-microbiota-brain axis by bile acids in depression. Psychiatry and Clinical Neurosciences, 76(7): 281. doi: 10.1111/pcn.13370
[12]	Hwang Y, Kim J, Shin JY, Kim JI, Seo JS, Webster MJ, et al. 2013. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Translational Psychiatry, 3(10): e321. doi: 10.1038/tp.2013.94
[13]	Lanz TA, Reinhart V, Sheehan MJ, Rizzo SJS, Bove SE, James LC, et al. 2019. Postmortem transcriptional profiling reveals widespread increase in inflammation in schizophrenia: a comparison of prefrontal cortex, striatum, and hippocampus among matched tetrads of controls with subjects diagnosed with schizophrenia, bipolar or major depressive disorder. Translational Psychiatry, 9(1): 151. doi: 10.1038/s41398-019-0492-8
[14]	Lei FY, Cui NW, Zhou CX, Chodosh J, Vavvas DG, Paschalis EI. 2020. CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages. Proceedings of the National Academy of Sciences of the United States of America, 117(38): 23336−23338. doi: 10.1073/pnas.1922788117
[15]	Livak KJ & Schmittgen TD. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4): 402-408.
[16]	Ma XK, Chen K, Cui YH, Huang GQ, Nehme A, Zhang L, et al. 2020. Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development, functional connectivity, and critical period plasticity. Journal of Neuroscience Research, 98(10): 1968−1986. doi: 10.1002/jnr.24641
[17]	McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O'Hely M, et al. 2022. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Molecular Psychiatry, 27(4): 1920−1935. doi: 10.1038/s41380-022-01456-3
[18]	Najafi AR, Crapser J, Jiang S, Ng W, Mortazavi A, West BL, et al. 2018. A limited capacity for microglial repopulation in the adult brain. Glia, 66(11): 2385−2396. doi: 10.1002/glia.23477
[19]	Nguyen R, Morrissey MD, Mahadevan V, Cajanding JD, Woodin MA, Yeomans JS, et al. 2014. Parvalbumin and GAD65 interneuron inhibition in the ventral hippocampus induces distinct behavioral deficits relevant to schizophrenia. Journal of Neuroscience, 34(45): 14948−14960. doi: 10.1523/JNEUROSCI.2204-14.2014
[20]	Ni RJ, Gao TH, Wang YY, Tian Y, Wei JX, Zhao LS, et al. 2022. Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway. Zoological Research, 43(6): 989−1004. doi: 10.24272/j.issn.2095-8137.2022.278
[21]	Ni RJ, Shu YM, Wang J, Yin JC, Xu L, Zhou JN. 2014. Distribution of vasopressin, oxytocin and vasoactive intestinal polypeptide in the hypothalamus and extrahypothalamic regions of tree shrews. Neuroscience, 265: 124−136. doi: 10.1016/j.neuroscience.2014.01.034
[22]	Ni RJ, Tian Y, Dai XY, Zhao LS, Wei JX, Zhou JN, et al. 2020. Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory. Zoological Research, 41(3): 258−272. doi: 10.24272/j.issn.2095-8137.2020.034
[23]	Oosterhof N, Kuil LE, van der Linde HC, Burm SM, Berdowski W, van Ijcken WFJ, et al. 2018. Colony-stimulating factor 1 receptor (CSF1R) regulates microglia density and distribution, but not microglia differentiation in vivo. Cell Reports, 24(5): 1203–1217. e6.
[24]	Smith BL, Laaker CJ, Lloyd KR, Hiltz AR, Reyes TM. 2020. Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet. Brain, Behavior, and Immunity, 84: 80−89. doi: 10.1016/j.bbi.2019.11.010
[25]	Svoboda J, Stankova A, Entlerova M, Stuchlik A. 2015. Acute administration of MK-801 in an animal model of psychosis in rats interferes with cognitively demanding forms of behavioral flexibility on a rotating arena. Frontiers in Behavioral Neuroscience, 9: 75.
[26]	VanRyzin JW, Arambula SE, Ashton SE, Blanchard AC, Burzinski MD, Davis KT, et al. 2021. Generation of an Iba1-EGFP transgenic rat for the study of microglia in an outbred rodent strain. eNeuro, 8(5): ENEURO.0026−21.2021.
[27]	Vichaya EG, Malik S, Sominsky L, Ford BG, Spencer SJ, Dantzer R. 2020. Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. Journal of Neuroinflammation, 17(1): 172. doi: 10.1186/s12974-020-01832-2
[28]	Volk DW. 2017. Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia. Neurobiology of Disease, 99: 58−65. doi: 10.1016/j.nbd.2016.12.019
[29]	Walther S, Stegmayer K, Federspiel A, Bohlhalter S, Wiest R, Viher PV. 2017. Aberrant hyperconnectivity in the motor system at rest is linked to motor abnormalities in schizophrenia spectrum disorders. Schizophrenia Bulletin, 43(5): 982−992. doi: 10.1093/schbul/sbx091
[30]	Warden AS, Wolfe SA, Khom S, Varodayan FP, Patel RR, Steinman MQ, et al. 2020. Microglia control escalation of drinking in alcohol-dependent mice: genomic and synaptic drivers. Biological Psychiatry, 88(12): 910−921. doi: 10.1016/j.biopsych.2020.05.011
[31]	Wegrzyn D, Juckel G, Faissner A. 2022. Structural and functional deviations of the hippocampus in schizophrenia and schizophrenia animal models. International Journal of Molecular Sciences, 23(10): 5482. doi: 10.3390/ijms23105482
[32]	Yang Y, Eguchi A, Wan XY, Chang LJ, Wang XM, Qu YG, et al. 2023. A role of gut-microbiota-brain axis via subdiaphragmatic vagus nerve in depression-like phenotypes in Chrna7 knock-out mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 120: 110652. doi: 10.1016/j.pnpbp.2022.110652
[33]	Yang Y, Ishima T, Wan XY, Wei Y, Chang LJ, Zhang JC, et al. 2022. Microglial depletion and abnormalities in gut microbiota composition and short-chain fatty acids in mice after repeated administration of colony stimulating factor 1 receptor inhibitor PLX5622. European Archives of Psychiatry and Clinical Neuroscience, 272(3): 483−495. doi: 10.1007/s00406-021-01325-0
[34]	Yao W, Cao QQ, Luo SL, He LJ, Yang C, Chen JX, et al. 2022a. Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine. Molecular Psychiatry, 27(3): 1618−1629. doi: 10.1038/s41380-021-01377-7
[35]	Yao ZY, Li XH, Zuo L, Xiong Q, He WT, Li DX, et al. 2022b. Maternal sleep deprivation induces gut microbial dysbiosis and neuroinflammation in offspring rats. Zoological Research, 43(3): 380−390. doi: 10.24272/j.issn.2095-8137.2022.023
[36]	Yegla B, Boles J, Kumar A, Foster TC. 2021. Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats. Glia, 69(6): 1494−1514. doi: 10.1002/glia.23975
[37]	Zhang K, Yang C, Chang LJ, Sakamoto A, Suzuki T, Fujita Y, et al. 2020. Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1. Translational Psychiatry, 10(1): 32. doi: 10.1038/s41398-020-0733-x
[38]	Zhang L, Shirayama Y, Iyo M, Hashimoto K. 2007. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology, 32(9): 2004−2010. doi: 10.1038/sj.npp.1301313
[39]	Zhao XF, Alam MM, Liao Y, Huang TT, Mathur R, Zhu XJ, et al. 2019. Targeting microglia using Cx3cr1-Cre lines: revisiting the specificity. eNeuro, 6(4): ENEURO.0114−19.2019.