Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

  1. Chuyu Chen
  2. Giulia Soto
  3. Vasin Dumrongprechachan
  4. Nicholas Bannon
  5. Shuo Kang
  6. Yevgenia Kozorovitskiy  Is a corresponding author
  7. Loukia Parisiadou  Is a corresponding author
  1. Feinberg School of Medicine, Northwestern University, United States
  2. Northwestern University, United States

Abstract

LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose towards disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using 2-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset.

Data availability

All data generated during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chuyu Chen

    Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Giulia Soto

    Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Vasin Dumrongprechachan

    Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicholas Bannon

    Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shuo Kang

    Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yevgenia Kozorovitskiy

    Department of Neurobiology, Northwestern University, Evanston, United States
    For correspondence
    Yevgenia.Kozorovitskiy@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3710-1484
  7. Loukia Parisiadou

    Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    For correspondence
    loukia.parisiadou@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2569-4200

Funding

National Institute of Neurological Disorders and Stroke (R01NS097901)

  • Loukia Parisiadou

Michael J. Fox Foundation for Parkinson's Research (LRRK2 Challenge)

  • Loukia Parisiadou

National Institute of Neurological Disorders and Stroke (R01NS107539)

  • Yevgenia Kozorovitskiy

Rita Allen Foundation (Rita Allen Scholar Award)

  • Yevgenia Kozorovitskiy

Kinship Foundation (Searle Scholar Award)

  • Yevgenia Kozorovitskiy

Arnold and Mabel Beckman Foundation (Beckman Young Investigator Award)

  • Yevgenia Kozorovitskiy

National Institute of Neurological Disorders and Stroke (F32NS103243)

  • Nicholas Bannon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse experiments were approved by Northwestern University Animal Care and Use Committee (Approved protocol numbers IS000035451, IS00000838, and 00009022).

Reviewing Editor

  1. Carl Lupica

Publication history

  1. Received: May 16, 2020
  2. Accepted: October 1, 2020
  3. Accepted Manuscript published: October 2, 2020 (version 1)
  4. Version of Record published: November 3, 2020 (version 2)

Copyright

© 2020, Chen 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. Chuyu Chen
  2. Giulia Soto
  3. Vasin Dumrongprechachan
  4. Nicholas Bannon
  5. Shuo Kang
  6. Yevgenia Kozorovitskiy
  7. Loukia Parisiadou
(2020)
Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations
eLife 9:e58997.
https://doi.org/10.7554/eLife.58997
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