A thalamostriatal brake counteracts cortical recruitment of striatal ensembles in levodopa-induced dyskinesia

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Abstract excerpt

Levodopa-induced dyskinesia (LID) is a disabling complication of Parkinson's disease therapy, yet how upstream circuits recruit and restrain dyskinesia-linked striatal ensembles remains unclear. Using FosTRAP-based ensemble access in a unilateral 6-hydroxydopamine mouse model, we identified secondary motor cortex (M2) and parafascicular thalamus (PF) as dominant afferents with opposing functions. Projection-wide M2 activation promoted dyskinesia, whereas PF activation suppressed ongoing dyskinesia and shifted behavior toward non-dyskinetic states. Chronic levodopa reduced overall presynaptic terminal abundance while preserving putative contacts onto ensemble neurons, thereby increasing effective pathway-to-ensemble coupling. This remodeling followed distinct pathway rules: M2 contacts became spatially dispersed and biased toward NMDAR-mediated excitation, whereas PF inputs recruited stronger polysynaptic inhibition. Dyskinesia preferentially re-engaged ensemble-projecting M2 neurons, but reactivated PF neurons were topographically segregated from PF neurons directly innervating the ensemble. Accordingly, selective M2-to-ensemble stimulation promoted dyskinesia, whereas selective PF-to-ensemble stimulation was ineffective. Finally, ensemble-restricted Grin1 knockdown reduced peak dyskinesia and weakened M2-driven dyskinesia. These findings define LID as a targetable imbalance between cortical ensemble recruitment and thalamostriatal restraint.