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, although protein loss suggests a role in glutamatergic sy...

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Bibliographic Details
Published in:Human molecular genetics 2015-03, Vol.24 (5), p.1336-1349
Main Authors: Beccano-Kelly, Dayne A, Volta, Mattia, Munsie, Lise N, Paschall, Sarah A, Tatarnikov, Igor, Co, Kimberley, Chou, Patrick, Cao, Li-Ping, Bergeron, Sabrina, Mitchell, Emma, Han, Heather, Melrose, Heather L, Tapia, Lucia, Raymond, Lynn A, Farrer, Matthew J, Milnerwood, Austen J
Format: Article
Language:English
Subjects:
Animals
Dopamine - metabolism
Glutamates
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Male
Memory
Mice
Mice, Transgenic
Motor Activity
Neostriatum - metabolism
Neuronal Plasticity
Neurons - metabolism
Parkinson Disease - genetics
Phosphoproteins - genetics
Phosphoproteins - metabolism
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Receptors, Dopamine D2 - genetics
Receptors, Dopamine D2 - metabolism
Signal Transduction
Synaptic Transmission
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddu543