Study Probes Key Receptor Signaling That Goes Awry in Parkinson

According to a recent study, dopamine receptor D3 (DRD3) signaling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, favoring microglial activation and promoting neuroinflammation—the pathogenic process leading to neurodegeneration in many disorders, including Parkinson disease.

The research, published in the Journal of Neuroinflammation, investigated how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation. The researchers induced neuroinflammation by intraperitoneal administration of lipopolysaccharide (LPS) in animal models. Immunohistochemistry and flow cytometry was used to determine the effect of genetic DRD3-deficiency or pharmacologic DRD3-antagonism in the functional phenotype of astrocytes and microglia.

“Emerging evidence indicates that neuroinflammation plays a pivotal role in the cascade of events leading to neuronal death and progression of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease,” the authors said. “Consequently, the functional phenotype acquired by microglia determines whether surrounding neurons survive or die. Accordingly, depending on the integration of different molecular cues, microglial cells might acquire two different phenotypes, including an inflammatory M1 phenotype and an anti-inflammatory M2 phenotype.”

The study results indicated that DRD3 was in astrocytes but not in microglial cells. In addition, DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation, according to the results.

The researchers also found similar alterations in the functional phenotypes of glial cells by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge.

“Our findings here show genetic and pharmacologic evidence demonstrating how dopaminergic signalling mediated through DRD3 regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, ultimately promoting neuroinflammation,” concluded the authors. “Lack of DRD3 signalling induced unresponsiveness of astrocytes with attenuated microglial activation and an early increase of the M1-to-M2 ratio in the phenotype of microglia in response to inflammatory stimuli, which finally resulted in dampening neuroinflammation.”

This research represents the first study demonstrating how DRD3 signalling regulate the dynamics of glial activation and impact neuroinflammation.

Reference

Montoya A, Elgueta D, et al. Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation [published online 2019]. J Neuroinflammation. doi: 10.1186/s12974-019-1652-8.