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Hum Mol Genet. 2015 Mar 1;24(5):1336-49. doi: 10.1093/hmg/ddu543. Epub 2014 Oct 24.

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

Author information

Centre for Applied Neurogenetics, Brain Research Centre.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada V6T 2B5.
Centre for Applied Neurogenetics, Brain Research Centre, Department of Medical Genetics.
Centre for Applied Neurogenetics, Division of Neurology, Brain Research Centre,


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.

[Indexed for MEDLINE]

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