Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment

Abstract

These experiments re-examined the notion that reduced activity in the external pallidal segment (GPe) results in the abnormalities of neuronal discharge in the subthalamic nucleus (STN) and the internal pallidal segment (GPi) and in the development of parkinsonian motor signs. Extracellular recording in two rhesus monkeys, which had been rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed that the average neuronal discharge rate decreased in GPe but increased in STN and GPi. After MPTP, neurons in all three nuclei tended to discharge in oscillatory bursts. In addition, GABA release in STN (measured with microdialysis) was reduced, indicative of reduced activity along the GPe-STN pathway. Finally, the concentration of glutamic acid dehydrogenase (GAD; measured with autoimmunoradiography) was increased in GPe and GPi, likely reflecting increased striatal input and increased activity of local axon collaterals, respectively. Surprisingly, GAD protein in STN remained unchanged, indicating that the usual assumption that GAD levels are determined primarily by the overall activity of GABAergic elements may be too simplistic. The results from the MPTP-treated animals were compared with results obtained in a second group of three animals with ibotenic acid lesions of GPe. GPe lesions resulted in increased discharge in STN and GPi, comparable with the changes seen after MPTP but did not induce oscillatory bursting and had no behavioral effects. The results indicate that a mere reduction of GPe activity does not produce parkinsonism. Other changes, such as altered discharge patterns in STN and GPi, may play an important role in the generation of parkinsonism.

Figure 3.

GABA concentrations in the STN as measured with microdialysis in monkeys H and I, before (black columns) and after (gray columns) treatment with MPTP. A and B show the average GABA levels by sample number in the two monkeys. Per our microdialysis protocol, sample 6 was exposed to 80 mm K⁺, resulting in a significant increase in the GABA level. C depicts the average absolute baseline GABA levels in the two monkeys. ^*p < 0.05 versus the baseline level in the normal state.

Figure 5.

Extent of ibotenic acid-induced lesion aimed at GPe. Histological and electrophysiological data were used to reconstruct the location of the ibotenic acid injections in these serial coronal sections. The approximate anterior coronal plane number is shown in the top right corner of each diagram. As indicated in the diagram in the bottom left corner, the dark gray structures indicate the extent of the putamen, the medium gray structure indicates the extent of GPe, and the light gray structure indicates the extent of GPi. The lesions are shown as semitransparent overlays. The dashed line in the drawing in the bottom left corner shows the angle of approach to the pallidum, which was used for recording and lesioning penetrations.

Figure 1.

Comparison of changes in neuronal discharge in GPe, STN, and GPi in parkinsonian and GPe-lesioned primates. A, Changes in average discharge rates. The black columns show the discharge rates (mean ± SEM) under normal conditions; the light gray columns were derived from data of monkeys H and I after treatment with MPTP, and the dark gray columns were derived from monkeys F, K, and X after placement of GPe lesions. B, Changes in the percentage of neuronal discharge detected within bursts. Same conventions as in A. ^*p < 0.05 versus data in the normal state. See text for n numbers.

Figure 2.

Comparison of oscillatory neuronal activity in GPe, STN, and GPi in parkinsonian and GPe-lesioned animals. A, Integrated power spectra. Shown are the ratios of integrated power found in the 3-8 Hz (A1) and 8-15 Hz (A2) ranges to the total power found in power spectra of neuronal activity, computed between 1 and 50 Hz (see Materials and Methods for computation and Results for additional details). B, Autocorrelation analysis. The columns depict the proportion of cells with three or more peaks in the autocorrelograms of their discharge, divided into different frequency ranges (B1, 3-8 Hz range; B2, 8-15 Hz range). ^*p < 0.05.

Figure 4.

TH and GAD-IR in the basal ganglia. A, Macrograph showing TH-IR in the striatum (St) of monkey H. Note the presence and absence of TH-IR in the striatum in the control and lesioned sides, respectively. B, The same section was double labeled for GAD by immunoautoradiography. The gray levels have been converted to a pseudocolor scale, wherein red color depicts high immunoreactivity and blue depicts low immunoreactivity. Note the increase in GAD-IR in GPe and GPi on the lesioned side. The arrow indicates nonspecific staining along electrode and microdialysis tracts. C, Histograms depicting densitometric measurements of GAD-IR in GPe, STN, and GPi from the untreated (white columns) and MPTP-lesioned side (black columns). GAD-IR was quantified from immunoautoradiograms using the MCID image analysis system. GAD-IR is expressed as percentage control. ir, Immunoreactivity.