Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
Sarah E MacIsaac
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
Naila Kuhlmann
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada
Chelsie A Kadgien
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada
Igor Tatarnikov
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Jesse Fox
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Jaskaran Khinda
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Emma Mitchell
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Sabrina Bergeron
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Heather Melrose
Mayo Clinic, Jacksonville, United States
Matthew J Farrer
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada
LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.
