Parkinson’s disease (PD) involves genetic and environmental risk factors. Increasing research efforts have been made to understand how they interact to impair homeostasis and elevate risk. Inflammation could be one unifying factor. In this study, wild-type (WT) and overexpressing human α-synuclein (Snca+/+) rats were intraperitoneally injected with a single dose of lipopolysaccharide (LPS) or with saline (SAL). In these animals we assessed the development of PD-like symptoms by immunohistology, high-dimensional flow cytometry, electrophysiology, and behavioral analyses. A single injection of LPS to both WT and Snca+/+ rats triggered long-lasting increased activation of pro-inflammatory microglial markers, infiltrating monocytes and T-lymphocytes. However, only LPS Snca+/+ rats displayed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction of evoked dopamine release in the striatum. No significant changes were observed in the behavioral domain.