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).

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.

Metrics

  • 2,792
    views
  • 394
    downloads
  • 46
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.58997

Further reading

    1. Neuroscience
    Gergely F Turi, Sasa Teng ... Yueqing Peng
    Research Article

    Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

    1. Neuroscience
    Ulrike Pech, Jasper Janssens ... Patrik Verstreken
    Research Article

    The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.