---
title: "Alpha-synuclein Overexpression Selectively Impairs Nigrostriatal Dopamine and Glutamate Transmissi"
id: "biorxiv-13-the-impact-of-alpha-synuclein-overexpression-on-nigrostriatal-transmission"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-13-the-impact-of-alpha-synuclein-overexpression-on-nigrostriatal-transmission"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.15.751842v1?rss=1"
published_at: "2026-09-21T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Alpha-synuclein Overexpression Selectively Impairs Nigrostriatal Dopamine and Glutamate Transmissi
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-13-the-impact-of-alpha-synuclein-overexpression-on-nigrostriatal-transmission
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.15.751842v1?rss=1)
- **Published At:** 2026-09-21T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study selectively overexpressed wild-type human **alpha-synuclein** in dopamine neurons of the **Substantia Nigra pars compacta (SNc)** to probe early functional consequences before overt neurodegeneration. - Overexpression produced a robust reduction in evoked **dopamine** release in the **dorsolateral striatum**, indicating presynaptic impairment of axonal dopamine output. - Despite reduced dopamine release, synaptic transmission onto postsynaptic medium spiny neurons (MSNs) remained functionally intact, suggesting preserved postsynaptic responsiveness or compensatory mechanisms. - **Glutamate** co-release from SNc axon terminals was selectively impaired onto both MSNs and striatal cholinergic interneurons, identifying a specific deficit in excitatory cotransmission. - **GABA** co-release from dopamine terminals was unaffected by synuclein overexpression, indicating neurotransmitter-specific vulnerability. - Somatodendritic **dopamine** release within the SNc was completely abolished by synuclein overexpression, showing a distinct susceptibility of somatodendritic compartments. - Behavioral analysis linked these transmission changes to impairments in locomotion, implying functional consequences of early synuclein accumulation. - The data indicate selective functional deficits in nigrostriatal signaling associated with wild-type synuclein accumulation prior to cell loss and raise the possibility of compensatory adaptations shaping early Parkinson’s disease–related dysfunction. - The work is reported as a preprint (not peer reviewed) and was funded by NIH R01-NS138043 and Aligning Science Across Parkinson’s; authors declared no competing interests.
## Clinical Analysis & Structured Key Points
The impact of alpha synuclein overexpression on nigrostriatal transmission | bioRxiv Skip to main content New Results The impact of alpha synuclein overexpression on nigrostriatal transmission View ORCID Profile Nikolas Bergum , View ORCID Profile Andrew Yee , View ORCID Profile Robert Edwards , View ORCID Profile Christopher P. Ford doi: https://doi.org/10.64898/2026.09.15.751842 Nikolas Bergum 1 University of Colorado; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nikolas Bergum Andrew Yee 1 University of Colorado; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andrew Yee Robert Edwards 2 UCSF; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Robert Edwards Christopher P. Ford 3 University of Colorado Anschutz Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christopher P. Ford For correspondence: christopher.ford{at}cuanschutz.edu Abstract Info/History Metrics Preview PDF Abstract Accumulation of wild type synuclein in dopamine neurons of the Substantia Nigra pars compacta is a pathological hallmark of Parkinson's disease (PD), which commonly precedes neurodegeneration. Yet how synuclein accumulation affects nigrostriatal neurotransmission early in the progression of PD remains poorly understood. In addition to axonal dopamine release, SNc neurons also co-release GABA and glutamate from striatal axon terminals and release dopamine from their somatodendritic region. However, the selective vulnerability of these distinct functions to increased synuclein remains largely unexplored. Here, we selectively overexpressed wild type human synuclein in SNc dopamine neurons to examine impacts on nigrostriatal and somatodendritic transmission and correlated these changes to impairments in locomotion. We found that dopamine release in the dorsolateral striatum was robustly reduced, while transmission to postsynaptic medium spiny neurons remained intact. Glutamate co-release from dopamine terminals onto both medium spiny neurons and cholinergic interneurons was selectively impaired, while GABA co-release was unaffected. Conversely, somatodendritic dopamine release within the SNc was completely abolished by synuclein overexpression. Together, these findings identify selective deficits in nigrostriatal neurotransmission associated with wild type synuclein accumulation prior to overt degeneration and raise the possibility of compensatory adaptations shaping the early functional consequences of synuclein pathology in PD. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Institutes of Health , R01-NS138043 Aligning Science Across Parkinson's , 020529 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 21, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following The impact of alpha synuclein overexpression on nigrostriatal transmission Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share The impact of alpha synuclein overexpression on nigrostriatal transmission Nikolas Bergum , Andrew Yee , Robert Edwards , Christopher P. Ford bioRxiv 2026.09.15.751842; doi: https://doi.org/10.64898/2026.09.15.751842 Share This Article: Copy Citation Tools The impact of alpha synuclein overexpression on nigrostriatal transmission Nikolas Bergum , Andrew Yee , Robert Edwards , Christopher P. 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