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Abstract Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet whether these cells contribute to the motor deficits and neurodegeneration in PD remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice for 8 weeks via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Astrocyte activation and C3+-astrocyte (A1-reactive) numbers were also decreased, providing evidence that reactive astrogliosis is dependent on microglia in PD mice. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult.
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