title: LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory.
abstract: 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.
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Dayne A
authors.initials: DA
authors.lastname: Beccano-Kelly
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Mattia
authors.initials: M
authors.lastname: Volta
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Lise N
authors.initials: LN
authors.lastname: Munsie
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Paschall
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Igor
authors.initials: I
authors.lastname: Tatarnikov
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Co
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chou
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Cao
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bergeron
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Emma
authors.initials: E
authors.lastname: Mitchell
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Heather
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tapia
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada V6T 2B5.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.affiliation: Centre for Applied Neurogenetics, Brain Research Centre, Department of Medical Genetics.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.affiliation: Centre for Applied Neurogenetics, Division of Neurology, Brain Research Centre, amilnerwood@can.ubc.ca.
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Milnerwood
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D005971:Glutamates; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D017072:Neostriatum / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D009435:Synaptic Transmission
chemical_list: D005971:Glutamates; D010750:Phosphoproteins; D017448:Receptors, Dopamine D2; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine