LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory

Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson’s disease (PD), a neurodegenerative disorder affecting 1–2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, althoughproteinlosssuggestsaroleinglutamatergicsynapsetransmissionandoverexpressionstudiesshowaltereddopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreasedstriatal dopamine tone andabnormaldopamine- andcAMP-regulatedphosphoprotein32 kDasignalintegration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.