Parkinsonism disrupts cortical function by dysregulating oscillatory, network and synaptic activity of parvalbumin positive interneurons
Antea Minetti, Elena Montagni, Nicolò Meneghetti, Francesca Macchi, Éléa Coulomb, Alessandra Martello, Alexia Tiberi, Simona Capsoni, Alberto Mazzoni, Anna Letizia Allegra Mascaro, Cristina Spalletti
Abstract
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.