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

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

Version 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.

Metrics

  • 2,047
    Page views
  • 596
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

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. 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

Further reading

    1. Neuroscience
    Jing Wang, Hamid Azimi ... Gregor Rainer
    Research Article

    The lateral geniculate nucleus (LGN), a retinotopic relay center where visual inputs from the retina are processed and relayed to the visual cortex, has been proposed as a potential target for artificial vision. At present, it is unknown whether optogenetic LGN stimulation is sufficient to elicit behaviorally relevant percepts, and the properties of LGN neural responses relevant for artificial vision have not been thoroughly characterized. Here, we demonstrate that tree shrews pretrained on a visual detection task can detect optogenetic LGN activation using an AAV2-CamKIIα-ChR2 construct and readily generalize from visual to optogenetic detection. Simultaneous recordings of LGN spiking activity and primary visual cortex (V1) local field potentials (LFP) during optogenetic LGN stimulation show that LGN neurons reliably follow optogenetic stimulation at frequencies up to 60 Hz, and uncovered a striking phase locking between the V1 local field potential (LFP) and the evoked spiking activity in LGN. These phase relationships were maintained over a broad range of LGN stimulation frequencies, up to 80 Hz, with spike field coherence values favoring higher frequencies, indicating the ability to relay temporally precise information to V1 using light activation of the LGN. Finally, V1 LFP responses showed sensitivity values to LGN optogenetic activation that were similar to the animal's behavioral performance. Taken together, our findings confirm the LGN as a potential target for visual prosthetics in a highly visual mammal closely related to primates.

    1. Neuroscience
    Yuk-Hoi Yiu, Christian Leibold
    Research Article

    Hippocampal place cell sequences have been hypothesized to serve as diverse purposes as the induction of synaptic plasticity, formation and consolidation of long-term memories, or navigation and planning. During spatial behaviors of rodents, sequential firing of place cells at the theta timescale (known as theta sequences) encodes running trajectories, which can be considered as one-dimensional behavioral sequences of traversed locations. In a two-dimensional space, however, each single location can be visited along arbitrary one-dimensional running trajectories. Thus, a place cell will generally take part in multiple different theta sequences, raising questions about how this two-dimensional topology can be reconciled with the idea of hippocampal sequences underlying memory of (one-dimensional) episodes. Here, we propose a computational model of cornu ammonis 3 (CA3) and dentate gyrus (DG), where sensorimotor input drives the direction-dependent (extrinsic) theta sequences within CA3 reflecting the two-dimensional spatial topology, whereas the intrahippocampal CA3-DG projections concurrently produce intrinsic sequences that are independent of the specific running trajectory. Consistent with experimental data, intrinsic theta sequences are less prominent, but can nevertheless be detected during theta activity, thereby serving as running-direction independent landmark cues. We hypothesize that the intrinsic sequences largely reflect replay and preplay activity during non-theta states.