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bioRxiv · 10.64898/2026.09.15.751842

The impact of alpha synuclein overexpression on nigrostriatal transmission

Bergum, N.·Yee, A.·Edwards, R.·Ford, C. P.
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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.

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Bergum, N., Yee, A., Edwards, R., Ford, C. P.. 2026-09-21. The impact of alpha synuclein overexpression on nigrostriatal transmission. https://doi.org/10.64898/2026.09.15.751842

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