Parkinsonism disrupts cortical function by dysregulating oscillatory, network and synaptic activity of parvalbumin positive interneurons

Identifying novel and accessible therapeutic targets for Parkinson’s Disease (PD) remains a pressing goal. Growing evidence implicates cortical dysfunctions in PD-related symptoms, yet the mechanisms—especially those involving parvalbumin-positive interneurons (PV-INs), key regulators of brain oscillations and plasticity—are not fully understood. In this study, we investigate how PD alters PV-IN network and cortical oscillatory dynamics using the 6-hydroxydopamine (6-OHDA) mouse model. Through an integrated approach combining electrophysiological recordings, wide-field calcium imaging, and histological analysis, we reveal a profound cascade of cortical changes. These include pathological hyperactivity above 100 Hz during movement and severe disruptions in PV-IN connectivity across the motor cortex. Synaptic imbalances and microglial activation further point to a multifaceted cortical response to dopaminergic degeneration, revealing inhibitory dysfunction, oscillatory instability, structural remodeling, and neuroinflammation. Our results link PD to cortical instability and highlight cortical plasticity as a promising target for therapeutic intervention. (Figure presented.)