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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, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine 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 decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. 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.

Original publication

DOI

10.1093/hmg/ddu543

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/03/2015

Volume

24

Pages

1336 - 1349

Keywords

Animals, Dopamine, Glutamates, Male, Memory, Mice, Mice, Transgenic, Motor Activity, Neostriatum, Neuronal Plasticity, Neurons, Parkinson Disease, Phosphoproteins, Protein-Serine-Threonine Kinases, Receptors, Dopamine D2, Signal Transduction, Synaptic Transmission