Altered cortical network in Parkinson's Disease: the central role of PV interneuron and synaptic remodelling

Parkinson's disease (PD) is traditionally defined by the progressive degeneration of nigrostriatal dopaminergic neurons; however, accumulating evidence highlights extensive cortical dysfunctions as key contributors to motor and non-motor symptoms. Despite this growing recognition, the precise mechanisms underlying cortical network disruptions and their contribution to PD pathophysiology remain poorly understood, particularly in relation to parvalbumin-positive interneurons (PV-INs) and maladaptive plasticity. Here, we investigate the dysregulation of cortical network homeostasis in PD using a 6-hydroxydopamine (6-OHDA) mouse model, focusing on the progressive disruption of parvalbumin-positive interneuron (PV-IN) connectivity, excitatory/inhibitory balance, and neuroinflammatory responses. Using a multimodal approach integrating longitudinal electrophysiology, wide-field calcium imaging, and histological analyses, we revealed striking alterations in cortical activity and connectivity. Specifically, we observed pathological high-gamma hyperactivity during movement, accompanied by severe disruptions in PV-IN connectivity across motor and somatosensory cortices. Histological analyses further revealed synaptic imbalances and microglial dysregulation, suggesting an extensive cortical response to dopaminergic loss. These findings indicate that PV-IN dysfunction drives cortical maladaptive plasticity, leading to network desynchronization and motor deficits. By reframing PD as a disorder of cortical network homeostasis, this study provides novel mechanistic insights and identifies cortical plasticity as a promising therapeutic target for disease modification.