The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) until parkinsonian signs, including akinesia, rigidity, and a prominent 4- to 8-Hz tremor, appeared. The activity of neurons in the subthalamic nucleus (STN) and in the internal segment of the globus pallidus (GPi) was recorded before (STN, n = 220 cells; GPi, n = 175 cells) and after MPTP treatment (STN, n = 326 cells; GPi, n = 154 cells). 2. In STN the spontaneous firing rate was significantly increased from 19 ± 10 (SD) spikes/s before to 26 ± 15 spikes/s after MPTP treatment. Division of STN neurons recorded after MPTP treatment into cells with rhythmic bursts of discharge occurring at 4-8 Hz (as defined by autocorrelation analysis) and neurons without 4- to 8-Hz periodic activity revealed an even more prominent increase in the firing rate of the 4- to 8-Hz oscillatory neurons. 3. In GPi- overall changes in the average firing rate of cells were inconsistent between different animals and behavioral states. However, the average firing rate of the subpopulation of neurons with 4- to 8-Hz periodic oscillatory activity after treatment with MPTP was significantly increased over that of all neurons before MPTP treatment (from 53 to 76 spikes/s, averaged across monkeys). 4. In the normal state the percentage of neurons with burst discharges (as defined by autocorrelation analysis) was 69% and 78% in STN and GPi, respectively. After MPTP treatment the percentage of cells that discharged in bursts was increased to 79% and 89%, respectively. At the same time the average burst duration decreased (from 121 ± 98 to 81 ± 99 ms in STN and from 213 ± 120 to 146 ± 134 ms in GPi) with no significant change in the average number of spikes per burst. 5. Periodic oscillatory neuronal activity at low frequency, highly correlated with tremor, was detected in a large number of cells in STN and GPi after MPTP treatment (average oscillation frequency 6.0 and 5.1 Hz, respectively). The autocorrelograms of spike trains of these neurons confirm that the periodic oscillatory activity was very stable. The percentage of cells with 4- to 8-Hz periodic activity significantly increased from 2% to 16% in STN and from 0.6% to 25% in GPi with the MPTP treatment. 6. Neurons discharging with periodic bursts at frequencies between 8 and 20 Hz (average 14.4 Hz in STN and 10.5 Hz in GPi) were also detected more often after MPTP. The autocorrelograms of these neurons showed a high degree of dampening. The percentage of neurons with 8- to 20-Hz oscillations significantly increased from 0.7% to 10% in STN and from 0.6% to 12% in GPi after MPTP treatment. 7. The average magnitude and duration of phasic responses (increases and decrease in firing rate) to the application of flexion and extension torque pulses to the elbow tended to be increased after MPTP treatment in both STN and GPi. 8. The duration of extracellularly recorded action potentials significantly increased with the MPTP treatment (from 0.67 ± 0.1 to 0.81 ± 0.2 ms in STN and from 0.73 ± 0.1 to 0.8 ± 0.1 ms in GPi). 9. Tyrosine hydroxylase immunohistochemistry revealed that the striatum as well as STN and GPi of the MPTP-treated monkeys were virtually devoid of dopaminergic terminals. 10. These results support a model in which dopaminergic denervation of the basal ganglia (possibly including extrastriatal sites) leads to increased tonic and phasic activity in STN and GPi. Increased inhibition of thalamocortical neurons by GPi output may eventually result in akinesia and rigidity, whereas periodic oscillatory activity in the cortico-STN-GPi-thalamic circuitry is possibly involved in the development of parkinsonian tremor.