Synaptic location is a determinant of the detrimental effects of α-Synuclein pathology to glutamatergic transmission in the basolateral amygdala
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.
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
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.
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).
- Jun Ding, Stanford University, United States
- Preprint posted: February 20, 2022 (view preprint)
- Received: February 20, 2022
- Accepted: June 27, 2022
- Accepted Manuscript published: July 1, 2022 (version 1)
- Version of Record published: July 15, 2022 (version 2)
© 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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