Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

Abstract

BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

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