Synaptic location is a determinant of the detrimental effects of α-Synuclein pathology to glutamatergic transmission in the basolateral amygdala

  1. Liqiang Chen
  2. Chetan Nagaraja
  3. Samuel Daniels
  4. Zoe A Fisk
  5. Rachel Dvorak
  6. Lindsay Meyerdirk
  7. Jennifer A Steiner
  8. Martha L Escobar Galvis
  9. Michael X Henderson
  10. Maxime WC Rousseaux
  11. Patrik Brundin
  12. Hong-Yuan Chu  Is a corresponding author
  1. Van Andel Institute, United States
  2. University of Ottawa, Canada
  3. F. Hoffmann-La Roche, United States

Abstract

The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson’s disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

Data availability

All source data associated with the revised manuscript have been deposited on Open Science Framework: https://doi.org/10.17605/OSF.IO/264SM.All data generated or analyzed during this study are included in the manuscript and source data have been provided for all main and supplementary figures.

Article and author information

Author details

  1. Liqiang Chen

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3236-1129
  2. Chetan Nagaraja

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
  3. Samuel Daniels

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
  4. Zoe A Fisk

    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
    Competing interests
    No competing interests declared.
  5. Rachel Dvorak

    Department of Neurodegenerative Science, Van Andel Institute, GRand Rapids, United States
    Competing interests
    No competing interests declared.
  6. Lindsay Meyerdirk

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
  7. Jennifer A Steiner

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0953-1310
  8. Martha L Escobar Galvis

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8400-9392
  9. Michael X Henderson

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    Competing interests
    No competing interests declared.
  10. Maxime WC Rousseaux

    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
    Competing interests
    No competing interests declared.
  11. Patrik Brundin

    Pharma Research and Early Development (pRED), F. Hoffmann-La Roche, Little Falls, United States
    Competing interests
    Patrik Brundin, has received support as a consultant from AbbVie, Axial Therapeutics., Calico Life Sciences, CuraSen, Enterin Inc, Fujifilm-Cellular Dynamics International, Idorsia Pharmaceuticals, Lundbeck A/S. He has received commercial support for research from Lundbeck A/S and F. Hoffman-La Roche. He has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc and RYNE Biotechnology. During the time that this paper was undergoing revision he became an employee of F. Hoffman-La Roche, although none of the data were generated by this company..
  12. Hong-Yuan Chu

    Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, United States
    For correspondence
    hongyuan.chu@vai.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0923-683X

Funding

Brain and Behavior Research Foundation

  • Hong-Yuan Chu

Congressionally Directed Medical Research Programs

  • Hong-Yuan Chu

Aligning Science Across Parkinson's (ASAP-020616)

  • Michael X Henderson
  • Maxime WC Rousseaux
  • Hong-Yuan Chu

Aligning Science Across Parkinson's (ASAP-020625)

  • Maxime WC Rousseaux

Aligning Science Across Parkinson's (ASAP-020572)

  • Hong-Yuan Chu

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 animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at Van Andel Institute (animal use protocol#: 22-02-007).

Reviewing Editor

  1. Jun Ding, Stanford University, United States

Publication history

  1. Preprint posted: February 20, 2022 (view preprint)
  2. Received: February 20, 2022
  3. Accepted: June 27, 2022
  4. Accepted Manuscript published: July 1, 2022 (version 1)
  5. Version of Record published: July 15, 2022 (version 2)

Copyright

© 2022, 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. Liqiang Chen
  2. Chetan Nagaraja
  3. Samuel Daniels
  4. Zoe A Fisk
  5. Rachel Dvorak
  6. Lindsay Meyerdirk
  7. Jennifer A Steiner
  8. Martha L Escobar Galvis
  9. Michael X Henderson
  10. Maxime WC Rousseaux
  11. Patrik Brundin
  12. Hong-Yuan Chu
(2022)
Synaptic location is a determinant of the detrimental effects of α-Synuclein pathology to glutamatergic transmission in the basolateral amygdala
eLife 11:e78055.
https://doi.org/10.7554/eLife.78055
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