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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating
Rong-Jun Ni1,2, Yi-Yan Wang1,2, Tian-Hao Gao1,2
1Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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.
Insights
Microglial depletion using PLX3397 prevented MK-801 induced hyperactivity and schizophrenia-like behaviors in mice. These behavioral changes were linked to altered expression of inflammation-related genes, not glutamate or GABA genes.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- N-methyl-D-aspartate receptor (NMDAR) antagonists like MK-801 are used to model psychiatric disorders.
- The role of microglia and inflammation-related genes in these models is not well understood.
Purpose of the Study:
- To investigate the involvement of microglia and inflammation-related genes in MK-801 induced behavioral changes.
- To determine if microglial depletion affects MK-801 induced hyperactivity and schizophrenia-like behaviors.
Main Methods:
- Mice were treated with PLX3397 to deplete microglia and/or MK-801 to induce behavioral changes.
- Behavioral tests (open-field test) were conducted to assess hyperactivity and schizophrenia-like behaviors.
- Gene expression analysis of glutamate, GABA, and inflammation-related genes was performed.
Main Results:
- PLX3397-induced microglial depletion prevented MK-801 induced hyperactivity and associated behaviors.
- Microglial density correlated significantly with behavioral changes.
- Behavioral changes were strongly associated with the expression of specific inflammation-related genes, but not glutamate or GABA genes.
Conclusions:
- Microglial depletion can ameliorate NMDAR antagonist-induced hyperactivity.
- The protective effect is associated with the modulation of brain immune-related gene expression.
- This highlights the role of microglia and neuroinflammation in psychiatric disorder models.
