Quantifying Early Dendritic and Spine Remodeling in Premotor Parkinsonism Using Neurolucida 360

Merino-Galán L, Zamarbide M, Belloso-Iguerategui A, Alonso-Moreno MC, Gago B, Reinares-Sebastián A, Blesa J, Dumitriu D, Quiroga-Varela A, Rodríguez-Oroz MC. Resilience of striatal synaptic plasticity over early structural adaptations in premotor parkinsonism. NPJ Parkinsons Dis 2025;11(1):146. doi: 10.1038/s41531-025-00994-1.

Background: Parkinson’s disease involves progressive dopaminergic neuron loss in the substantia nigra and striatal dopamine depletion. Before motor symptoms appear, compensatory synaptic and structural adaptations may help maintain neural function, but their timing and mechanisms are unclear. Understanding these early changes in striatal spiny projection neurons (SPNs) is crucial for identifying premotor plasticity processes.

Hypothesis: This study hypothesized that early dopaminergic dysfunction induced by α-synuclein (A53T) overexpression impairs striatal synaptic plasticity and elicits compensatory structural remodeling of SPN dendrites before motor deficits emerge.

Methods: The authors used adult rats inoculated bilaterally in the substantia nigra with AAV vectors overexpressing A53T human α-synuclein and analyzed dopaminergic, synaptic and structural changes at 72 hours, 1, 2 and 4 weeks post-inoculation. Synaptic plasticity was assessed by FASS-LTP and neurotransmitter levels by HPLC. Dendritic spine morphology and dendritic arbor complexity were examined using high-resolution confocal microscopy and three-dimensional reconstruction with Neurolucida 360, while ultrastructural analyses were performed with electron microscopy.

Results: Dopamine content declined as early as 72 hours, accompanied by inhibition of chemical LTP, which partially recovered at four weeks. At this stage, dopaminergic neuron loss and fiber swelling became significant without motor deficits. Dendritic spine density decreased, particularly in thin spines, while mushroom spine head volume increased. Fewer spines contained smooth endoplasmic reticulum, though its relative area enlarged. SPNs displayed greater dendritic branching and complexity.

Conclusions: The results indicate that early dopaminergic dysfunction impairs striatal synaptic plasticity but triggers structural compensations in SPNs that may preserve network function. These adaptive spine and dendritic changes represent key homeostatic mechanisms sustaining striatal resilience during premotor parkinsonism.