Quinpirole ameliorates the dysfunction of microglia in human LRRK2-R1441G transgenic mice

Microglia-mediated neuroinflammation is a key contributor to Parkinson's disease (PD) pathogenesis. Leucine-rich repeat kinase 2 (LRRK2), the leading genetic contributor to both familial and sporadic PD, has been implicated in driving this connection. However, its precise role remains incompletely understood due to technical challenges. To address this, we utilized a bacterial artificial chromosome (BAC) transgenic mouse model overexpressing human LRRK2-R1441G, which replicates key features of PD. These mice were crossed with Cx3cr1-EGFP mice to enable assessment of microglial dynamics and function using two-photon imaging in awake mice in vivo and acute brain slices ex vivo . Furthermore, spatial transcriptomic analysis was performed using GeoMx Digital Spatial Profiler technology to compare transgenic mice with their wild-type counterparts. The R1441G mutation upregulated antigen processing and presentation pathways, increased activated microglia, and enhanced microglial polarization in the dorsal striatum. Mutant microglia exhibited reduced motility and slower responses to focal injury, with processes retracting faster and extending more slowly. Quinpirole, a dopamine D2 receptor (D2R) agonist, successfully reversed microglial deficits. This study provides the first evidence that pathogenic LRRK2 mutations alter microglial motility and responsiveness in vivo , highlighting D2R activation as a promising therapeutic strategy to mitigate neuroinflammation and neurodegeneration in PD.