Microglial activation contributes to depressive-like behavior in dopamine D3 receptor knockout mice |
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Institution: | 1. Department of Immunology and Pathogenic Biology, College of Basic Medicine, Xi''an Jiaotong University Health Science Center, Xi''an 710061, China;2. Forensic Medicine College of Xi''an Jiaotong University, Key Laboratory of the Health Ministry for Forensic Medicine, Xi''an 710061, China;3. Department of Laboratory, The Second Affiliated Hospital of Medical College of Xi''an Jiaotong University, Xi''an 710004, China;4. Graduate Teaching and Experiment Centre, Xi''an Jiaotong University Health Science Center, Xi''an 710061, China;5. Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202-9037, USA |
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Abstract: | We previously demonstrated that the dopamine D3 receptor (D3R) inhibitor, NGB2904, increases susceptibility to depressive-like symptoms, elevates pro-inflammatory cytokine expression, and alters brain-derived neurotrophic factor (BDNF) levels in mesolimbic dopaminergic regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) in mice. The mechanisms by which D3R inhibition affects neuroinflammation and onset of depression remain unclear. Here, using D3R-knockout (D3RKO) and congenic wild-type C56BL/6 (WT) mice, we demonstrated that D3RKO mice displayed depressive-like behaviors, increased tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels, and altered BDNF expression in selected mesolimbic dopaminergic regions. D3R expression was localized to astrocytes or microglia in the mPFC, NAc, and VTA in WT mice. D3RKO mice exhibited a large number of Iba1-labelled microglia in the absence of glial fibrillary acidic protein (GFAP)-labelled astrocytes in mesolimbic dopaminergic brain areas. Inhibition or ablation of microglia by minocycline (25 mg/kg and 50 mg/kg) or PLX3397 (40 mg/kg) treatment ameliorated depressive-like symptoms, alterations in pro-inflammatory cytokine levels, and BDNF expression in the indicated brain regions in D3RKO mice. Minocycline therapy alleviated the increase in synaptic density in the NAc in D3RKO mice. These findings suggest that microglial activation in selected mesolimbic reward regions affects depressive-like behaviors induced by D3R deficiency. |
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Keywords: | D3R Depressive-like behavior Microglia Pro-inflammatory cytokines BDNF Neuroplasticity |
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