Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice

  1. Mattia Volta
  2. Dayne A Beccano-Kelly
  3. Sarah A Paschall
  4. Stefano Cataldi
  5. Sarah E MacIsaac
  6. Naila Kuhlmann
  7. Chelsie A Kadgien
  8. Igor Tatarnikov
  9. Jesse Fox
  10. Jaskaran Khinda
  11. Emma Mitchell
  12. Sabrina Bergeron
  13. Heather Melrose
  14. Matthew J Farrer
  15. Austen J Milnerwood  Is a corresponding author
  1. Institute for Biomedicine, Italy
  2. University of Oxford, United Kingdom
  3. University of British Columbia, Canada
  4. Mayo Clinic, United States
  5. 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

  1. Mattia Volta

    Institute for Biomedicine, Bolzano, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0300-6796
  2. Dayne A Beccano-Kelly

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3592-8354
  3. Sarah A Paschall

    Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1440-4412
  4. Stefano Cataldi

    Graduate Program In Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7708-4124
  5. Sarah E MacIsaac

    Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Naila Kuhlmann

    Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Chelsie A Kadgien

    Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Igor Tatarnikov

    Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Jesse Fox

    Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Jaskaran Khinda

    Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Emma Mitchell

    Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Sabrina Bergeron

    Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Heather Melrose

    Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Matthew J Farrer

    Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Austen J Milnerwood

    Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada
    For correspondence
    austen.milnerwood@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0056-1778

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)

Reviewing Editor

  1. Andrew B West, University of Alabama at Birmingham, United States

Publication history

  1. Received: May 9, 2017
  2. Accepted: September 15, 2017
  3. Accepted Manuscript published: September 20, 2017 (version 1)
  4. Version of Record published: October 9, 2017 (version 2)
  5. Version of Record updated: November 2, 2017 (version 3)

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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  1. Mattia Volta
  2. Dayne A Beccano-Kelly
  3. Sarah A Paschall
  4. Stefano Cataldi
  5. Sarah E MacIsaac
  6. Naila Kuhlmann
  7. Chelsie A Kadgien
  8. Igor Tatarnikov
  9. Jesse Fox
  10. Jaskaran Khinda
  11. Emma Mitchell
  12. Sabrina Bergeron
  13. Heather Melrose
  14. Matthew J Farrer
  15. Austen J Milnerwood
(2017)
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

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