Transcriptional signatures of Striatal Spiny Projection Neuron Subtypes in Experimental Parkinsonism and Levodopa-Induced Dyskinesia

Parkinson’s disease (PD) causes major transcriptional and functional alterations in striatal circuitry following the loss of dopaminergic neurons in the substantia nigra pars compacta. Although levodopa (L-DOPA) is essential for managing motor symptoms, chronic treatment frequently leads to L-DOPA-induced dyskinesia (LID), a disabling motor complication. Most transcriptomic studies have focused on peak-dose dyskinesia, particularly in direct pathway spiny projection neurons (dSPNs), while the molecular landscape during the off-L-DOPA phase, when drug effects subside and motor symptoms re-emerge, remains poorly characterized. In a previous single-nucleus RNA sequencing (snRNA-seq) study using the 6-hydroxydopamine (6-OHDA) mouse model of PD, we identified the major striatal neuronal and non-neuronal populations and their responses to denervation and chronic L-DOPA during the off-state. Here, we performed a higher-resolution analysis of SPN subtypes using RNA markers of striatal compartmentalization and spatial distribution. This approach identified pathway, subtype, and compartment-specific transcriptional adaptations associated with dopaminergic loss and chronic L-DOPA exposure. Our findings provide a framework for understanding striatal circuit imbalance beyond peak-dose dyskinesia and highlight the off-L-DOPA phase as a critical, underexplored aspect of PD and LID pathophysiology.