Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice
- Institute for Biomedicine, Italy
- University of Oxford, United Kingdom
- University of British Columbia, Canada
- Mayo Clinic, United States
- Montreal Neurological Institute, McGill University, Canada
Abstract
LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine. Conversely, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across ages. Young GKI 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, dopamine transients are slower, independent of DAT, increasing dopamine extracellular lifetime. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI. 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.
Article and author information
Author details
Dayne A Beccano-Kelly
Austen J Milnerwood
Funding
Michael J. Fox Foundation for Parkinson's Research
- Matthew J Farrer
- Austen J Milnerwood
Parkinson Canada
- Mattia Volta
- Stefano Cataldi
- Chelsie A Kadgien
- Austen J Milnerwood
Canadian Institutes of Health Research
- Sarah E MacIsaac
- Igor Tatarnikov
Canada Excellence Research Chairs, Government of Canada
- Matthew J Farrer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were maintained according to Canadian Council on Animal Care regulations and the University of British Columbia Animal Ethics Committee (UBC AAC certification A16-0088 & A15-0105)
Copyright
© 2017, Volta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice
eLife 6:e28377.
https://doi.org/10.7554/eLife.28377
