Early nigrostriatal synaptic dysfunction underlies prodromal non-motor symptoms preceding dopaminergic neurodegeneration in an MPTP mouse model of Parkinson’s disease

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Abstract Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons; however, non-motor symptoms frequently emerge years before the onset of classical motor deficits. The biological mechanisms underlying these early manifestations remain poorly understood. Here, we investigated the temporal relationship between nigrostriatal degeneration, behavioural alterations, and neurotransmitter system changes using a slow-progressing MPTP mouse model that recapitulates key features of PD progression. We found that anxiety-like behaviour emerged at early stages of MPTP exposure, prior to detectable motor impairment. This behavioural phenotype coincided with significant loss of striatal tyrosine hydroxylase– and dopamine transporter–positive fibres, suggesting early presynaptic dopaminergic dysfunction. In contrast, significant dopaminergic neuronal loss in the substantia nigra pars compacta was observed only at later stages and was associated with the onset of motor deficits. MPTP treatment also induced early and sustained increases in total and phosphorylated α-synuclein, indicating that synaptic pathology accompanies early circuit dysfunction. While dopamine D1 and D2 receptor expression remained largely unchanged during disease progression, alterations in serotonergic and GABAergic markers were observed at later stages, suggesting secondary neurotransmitter adaptations. To examine clinical relevance, we analysed imaging and clinical data from the Parkinson’s Progression Markers Initiative (PPMI) cohort, which revealed early reductions in nigrostriatal dopamine transporter uptake together with increased anxiety measures in prodromal and early PD individuals. Together, these findings demonstrate that early nigrostriatal synaptic dysfunction is sufficient to drive prodromal non-motor symptoms prior to overt dopaminergic neuronal loss. Our results highlight early synaptic pathology as a potential substrate of prodromal PD and suggest a critical therapeutic window for disease-modifying interventions targeting early circuit dysfunction.

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