R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

Studies of two mouse models expressing different mutations of the LRRK2 gene, both associated with Parkinson's disease, reveals distinct alterations at electrochemical, electrophysiological, molecular, and behavioral levels. LRRK2 mutations are closely associated with Parkinson's disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations-G2019S and R1441C-we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations' impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.

Automated summary

Studies of mouse models with different mutations of the LRRK2 gene associated with Parkinson's disease reveal distinct alterations at multiple levels, including electrochemical, electrophysiological, molecular, and behavioral. The findings suggest that LRRK2 mutations affect striatal function, but the specific changes vary between different mutations. The results provide mechanistic insights for developing treatment strategies for Parkinson's disease patients.