Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia.

Parkinson's disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of Parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine-depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian monkeys. We found that systemic administration of l-3,4-dihydroxyphenylalanine (l-DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8-15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when Parkinsonian signs were alleviated and during l-DOPA-induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABA(A) receptor agonist). Intrapallidal microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; N-methyl-d-aspartate receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine-depleted state, glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson's disease.