Remodeling of Perineuronal Nets in the Striato-Cortical Axis in L-DOPA-Induced Dyskinesia Rat Model

L-DOPA-induced dyskinesia (LID) remains the most challenging complication of dopamine replacement therapy in Parkinson's disease, correlated with maladaptive plasticity within corticostriatal circuits. Perineuronal nets (PNNs), extracellular matrix structures enwrapping mainly parvalbumin interneurons (PV-INs), are key regulators of neuronal stability and plasticity, yet their contribution to LID is unknown. Using a unilateral 6-hydroxydopamine rat model of Parkinsonism followed by chronic L-DOPA administration, we quantified PNN-PV associations by Wisteria floribunda agglutinin (WFA) and PV immunolabeling across striatal and motor cortical territories. Dopamine loss markedly reduced PNN density and intensity in the dorsolateral striatum (DLS), which only partially recovered after L-DOPA. In LID, canonical WFA⁺/PV⁺ cells remained low, whereas non-canonical WFA^-/PV⁺ populations expanded in both DLS and M1 motor cortex (M1), indicating region-specific remodeling toward a high-plasticity state. To assess causality, we used Chondroitinase ABC (ChABC) for PNN degradation. DLS-targeted ChABC exacerbated abnormal involuntary movements and increased local PV density, while M1-ChABC had no behavioral effect but altered PV metrics within the DLS-M1 axis. These findings identify the DLS as a critical node where PNN fragility amplifies dyskinesia, highlight a functional coupling between striatal and cortical PNN-PV remodeling, and suggest that stabilizing extracellular matrix integrity could mitigate maladaptive plasticity underlying LID.