A single Citrobacter rodentium infection in Pink1 knockout and wild type mice leads to regional blood-brain-barrier perturbation and glial activation without dopamine neuron axon terminal loss

A growing body of research supports the hypothesis of links between immune system activation and the development of Parkinson’s disease (PD). A recent study revealed that repeated gastrointestinal infection with Citrobacter rodentium can lead to PD-like motor dysfunction in Pink1 knockout (KO) mice and immune cell entry in the brain. In the objective of better understanding the mechanisms leading to immune attack of the brain in this model, we evaluated here the hypothesis that such mild infections are sufficient to increase blood brain barrier (BBB) permeability and cause brain inflammation. Pink1 wild-type (WT) and KO mice were infected with Citrobacter rodentium and at day 13 and 26 post infection, we conducted gadolinium-enhanced magnetic resonance imaging (MRI) to identify signs of BBB permeability changes. Quantification of MRI results provided evidence of increased blood-brain barrier permeability in both WT and Pink1 KO at 26 days after the infection in the striatum, dentate gyrus, somatosensory cortex, and thalamus. This was not accompanied by any change in global expression of tight-junction proteins or in markers of the integrity of the dopamine (DA) system in the striatum at both time points. However, chronic microglial activation was detected at day 26 post infection, accompanied by an elevation of the inflammatory mediators eotaxin, IFNγ, CXCL9, IL-17 and MIP-2 in the striatum. Neutrophil infiltration in the brains of infected mice was also noted at day 26 post infection, as revealed by immune cell profiling by flow cytometry. Our results support the hypothesis that even after mild gastro-intestinal infection, increased BBB permeability could contribute to perturbations of brain homeostasis including increased microglial activation and the establishment of a chronic state of brain inflammation. Such perturbations could potentially act as a first hit for subsequent induction of PD pathology in the context of genetic vulnerability.