Accumulation of wild-type alpha-synuclein in dopamine neurons of the Substantia Nigra pars compacta (SNc) is a hallmark of Parkinson’s disease (PD) that often precedes neuronal loss. How such accumulation alters distinct modes of nigrostriatal neurotransmission early in disease progression remains incompletely understood. SNc dopamine neurons contribute to striatal signaling through axonal dopamine release, and also co-release GABA and glutamate from axon terminals. In addition, these neurons release dopamine from somatodendritic compartments within the SNc. The selective vulnerability of these separate transmission modes to synuclein accumulation has not been fully explored.
To address these questions, the investigators selectively overexpressed wild-type human alpha-synuclein in SNc dopamine neurons. The approach targeted the neuronal population known to underlie nigrostriatal projections, enabling comparisons between axonal dopamine transmission in the dorsolateral striatum, co-transmission of glutamate and GABA onto striatal targets, and somatodendritic dopamine release within the SNc. Functional measures were then correlated with locomotor behavior to assess the behavioral relevance of observed transmission changes. Details of experimental methods, such as viral constructs, expression levels, electrophysiological protocols, or exact behavioral assays, were not reported in the abstract.
The authors report a robust reduction in evoked dopamine release within the dorsolateral striatum following synuclein overexpression. This finding indicates a presynaptic impairment of axonal dopamine output from SNc neurons prior to overt neurodegeneration. The reduction in measurable dopamine release in this striatal subregion highlights an early functional deficit in the primary modulatory neurotransmitter associated with SNc neurons.
Despite the pronounced decrease in axonal dopamine release, synaptic transmission to postsynaptic medium spiny neurons (MSNs) remained intact. This dissociation between presynaptic dopamine availability and postsynaptic signaling suggests either that MSNs maintain responsiveness to remaining dopamine levels or that compensatory processes occur at the postsynaptic side or within network circuits. The persistence of MSN transmission despite reduced dopamine output points to selective vulnerabilities rather than global synaptic failure.
The study found a selective deficit in glutamate co-release from dopamine terminals. Glutamate co-transmission onto both medium spiny neurons and striatal cholinergic interneurons was impaired by synuclein overexpression. This selective loss of excitatory cotransmission identifies glutamate output as particularly susceptible to synuclein accumulation in SNc axons, and it suggests that different cotransmitters from the same axon terminals can be differentially affected.
In contrast to glutamate, GABA co-release from dopamine terminals was reported to be unaffected by synuclein overexpression. The preservation of inhibitory cotransmission alongside selective loss of excitatory cotransmission underscores neurotransmitter-specific effects of synuclein accumulation and supports the concept of distinct molecular or vesicular mechanisms governing release of different transmitters from the same axons.
A striking finding was the complete abolition of somatodendritic dopamine release within the SNc following alpha-synuclein overexpression. This result indicates that somatodendritic compartments are highly susceptible to the effects of synuclein accumulation, and that release mechanisms in these compartments may differ in vulnerability compared with axonal terminals. The loss of somatodendritic dopamine signaling could have local circuit consequences within the SNc that are separate from projections to the striatum.
The investigators correlated the observed transmission changes with impairments in locomotion, indicating that early functional deficits induced by synuclein accumulation have measurable behavioral consequences. The abstract does not provide detailed behavioral metrics or the magnitude of locomotor deficits; it reports only that locomotor impairment was associated with the transmission changes described.
Together, these findings identify selective deficits in nigrostriatal neurotransmission associated with accumulation of wild-type alpha-synuclein prior to overt degeneration. The differential effects—reduced axonal dopamine release in dorsolateral striatum, abolished somatodendritic dopamine release, impaired glutamate co-release, and preserved GABA co-release—suggest that synuclein pathology produces transmitter- and compartment-specific dysfunction. The preservation of postsynaptic transmission to MSNs despite reduced dopamine release raises the possibility of compensatory adaptations that may shape early functional consequences of synuclein accumulation in PD. These results point to early, selective synaptic dysfunction as a component of synuclein-related pathophysiology.
The work was supported by the National Institutes of Health (R01-NS138043) and Aligning Science Across Parkinson’s. The authors declared no competing interests. This article is posted as a preprint on bioRxiv and has not been certified by peer review. The abstract and summary herein reflect the content reported in the preprint; methodological specifics and detailed data were not included in the abstract and therefore are not described here.