Amantadine Modulates Action‐Specific Neural Ensembles in Hypokinetic and Hyperkinetic Conditions

Abstract Background In the classical model of basal ganglia circuitry, striatal spiny projection neurons of the direct and indirect pathways (dSPNs, iSPNs) promote and suppress movement, respectively, and exhibit unbalanced activity levels during hypokinetic or hyperkinetic conditions. Most therapies for these conditions are thought to work by rebalancing the relative activity of dSPNs and iSPNs toward normal levels. However, the mechanism of amantadine, which uniquely improves both hypokinetic and hyperkinetic conditions, is poorly understood. Objective Our aim was to determine whether amantadine restores motor function by normalizing the balance of dSPN and iSPN activity or through a distinct mechanism. Methods We used dual‐color two‐photon Ca 2+ imaging in the 6‐hydroxydopamine (6‐OHDA) mouse model of Parkinson's disease to concurrently monitor dSPN and iSPN dynamics across healthy, hypokinetic (parkinsonian), and hyperkinetic (dyskinetic) conditions. Results We evaluated both dSPN/iSPN activity balance and action‐specific neural ensemble activity in the dorsolateral striatum. In hypokinetic conditions, levodopa rescued the dSPN/iSPN imbalance but failed to restore the disrupted activity of the locomotion‐specific ensemble. Conversely, amantadine improved locomotion‐specific ensemble activity without normalizing the dSPN/iSPN imbalance. In hyperkinetic conditions, forelimb dyskinesias were characterized by neural activity patterns distinct from those encoding locomotion. Amantadine selectively suppressed the resting activity of forelimb dyskinesia ensembles without affecting locomotion‐coding ensembles or restoring pathway balance. Conclusions Levodopa and amantadine may act through distinct mechanisms, with levodopa normalizing pathway balance and amantadine modulating action‐specific neural ensembles. These findings support the importance of action‐coding disruptions during hypokinetic and hyperkinetic conditions and suggest that correcting them can restore motor function. © 2026 International Parkinson and Movement Disorder Society.