Objective: To define the anatomical and functional connectivity of the DCN-PPN pathway, determine its alterations in PD, and investigate whether impaired synaptic plasticity in this pathway contributes to motor dysfunction.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremor, bradykinesia, rigidity, and other motor deficits. Although dopamine replacement therapy and deep brain stimulation can relieve symptoms, their efficacy declines as the disease progresses. Most PD studies have focused on basal ganglia dysfunction, especially injury to the nigrostriatal dopaminergic system. However, growing evidence indicates that the cerebellum and related circuits also contribute to PD pathophysiology. Our previous studies showed dynamic changes in the superior cerebellar peduncle in PD patients, suggesting a compensatory role of cerebellar pathways in motor control. These findings support the deep cerebellar nucleus (DCN)-pedunculopontine nucleus (PPN) pathway as a potential therapeutic target.

Method: Anterograde and retrograde viral tracing was used to map projections from DCN subnuclei to the PPN. Immunofluorescence, three-dimensional electron microscopy, optogenetics, and whole-cell patch-clamp recording were used to characterize synaptic connectivity and properties. In an MPTP-induced PD mouse model, fiber photometry with GCaMP6s was used to monitor DCN-PPN neuronal activity. Chemogenetic activation or inhibition was applied to assess effects on motor deficits. In PD mouse brain slices, optogenetic stimulation combined with receptor antagonists was used to evaluate LTP/LTD and receptor-dependent synaptic plasticity.

Results: Clinical neuroimaging showed reduced structural connectivity between the dentate nucleus and PPN in PD patients, which was associated with greater motor symptom severity. DCN glutamatergic neurons formed monosynaptic projections to the PPN. In PD mice, neuronal activity in the DCN-PPN pathway was reduced, whereas targeted activation of this pathway improved motor deficits.

Conclusion: The DCN-PPN pathway contributes to motor regulation under physiological conditions. In PD, impaired synaptic plasticity weakens functional connectivity in this pathway and aggravates motor dysfunction. Targeted activation of the DCN-PPN pathway may represent a potential therapeutic strategy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dcn-ppn-pathway-activation-improves-motor-dysfunction-via-synaptic-plasticity-in-parkinsons-disease/