Enhancement of D1 dopaminergic responses in aged LRRK2 G2019S knock-in mice

LRRK2 G2019S is associated with familial and sporadic Parkinson's disease and G2019S knock-in mice represent a valuable model to study early changes of basal ganglia transmission associated with Parkinson's disease. Here, we performed behavioral, biochemical and neurochemical analysis in 3-month-old and 12-month-old G2019S knock-in (KI) mice to investigate whether the G2019S mutation is associated with changes of D1 transmission during ageing. Behavioral analysis revealed no difference across genotypes at 3 months but elevated grooming activity in 12-month-old G2019S KI mice compared to wild-type and LRRK2 kinase-dead mice. Immunoblotting revealed a two-fold increase of the levels of phosphorylated GluA1 subunit of the AMPA receptor in 12-month-old G2019S KI mice challenged with the D1 receptor agonist SKF-81297 (5 mg/Kg), compared to wild-type mice. In vivo dual probe microdialysis revealed elevations of basal striatal and nigral extracellular glutamate levels and reduction of nigral GABA levels in 12-month-old G2019S KI mice. Systemic administration of the D1 receptor agonist SKF-81297 did not affect neurotransmitter release whereas reverse dialysis of the D1 receptor antagonist SCH-23390 (10-1000 nM) elevated striatal GABA release in 12-month-old G2019S KI but not wild-type mice. Intrastriatal SCH-233390 was also associated with a prolonged reduction of glutamate release in the substantia nigra reticulata in both genotypes. Finally, 12-month-old G2019S KI mice showed a more prolonged hypokinetic response to intraperitoneal administration of SCH-23390 (1 mg/Kg) compared to wild-type mice. We conclude that the LRRK2 G2019S mutation is associated with age-dependent enhancement of D1 dopaminergic responses, possibly due to elevated endogenous D1 transmission in striatum, that might be instrumental to sustain motor and cognitive function over ageing and help explain the slower and more benign course of G2019S-associated Parkinson's disease.