Synaptic innervation of neurons in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys

In order to better understand the way by which the subthalamic nucleus interacts with the globus pallidus to control the output of the basal ganglia, we carried out a series of experiments to investigate the pattern of synaptic innervation of the pallidal neurons by the subthalamic terminals in the squirrel monkey. To address this problem we used the anterograde transport of biocytin. Following injections of biocytin in the subthalamic nucleus, rich plexuses of labelled fibres and varicosities formed bands that lay along the medullary lamina in both segments of the ipsilateral pallidum. At the electron microscopic level, two populations of bioctyin-containing terminals were identified in the internal pallidum (GPi). A first group of small to medium-sized terminals (type 1) mean cross-sectional area ±S. D. = 0.41 ± 0.04 μm² contained round vesicles and formed asymmetric synapses with dendritic shafts (95%) of mixed sizes (maximum diameter ranging from 0.3 to 4.0 μm) and spine-like structures (5%). This second group of terminals (type 2) contained pleiomorphic vesicles, had a larger cross-sectional area (mean ± S. D. = 0.9 ± 0.4 μm²) and formed symmetric synapses predominantly with perikarya (41%) and large dendrites (57%). In some cases, the two types of terminals converged at the level of single GPi neurons. Postembedding immunogold method revealed that the type 2 terminals displayed gamma-aminobutyric acid (GABA) immunoreactivity, whereas the type 1 terminals did not. In the external pallidum (GPe), injections in the subthalamic nucleus labelled both type 1 or type 2 terminals. However, the labelled type 2 boutons were much less abundant in GPe than in GPi. The presence of biocytin-labelled perikarya in GPe and the fact that the type 2 terminals displayed GABA immunoreactivity led us to suspect that these terminals were derived from axons of GPe neurons. In agreement with this hypothesis, injctions of Phaseolus vulgaris-leucoagglutinin (PHA-L) in GPe labelled terminals in GPi that displayed the morphological features and a pattern of synaptic organization similar to the type 2 terminals. In conclusion, the results of our study demonstrate that the subthalamopallidal terminals form asymmetric synapses that are distributed along the dendritic tree of GPe and Gpi neurons. In contrast, the GPe projection to GPi give rise to large GABA-containing terminals that form symmetric synapses predominantly with the proximal region of pallidal neurons. Because the GABAergic axon terminals from GPe form synapses onto the perikarya and proximal dendrites of GPi neurons, the Gpe input is in a strategic position to reduce the excitatory influence generated more distally on the dendritic tree by the subthalamic nucleus. © 1994 Wiley-Liss, Inc.     

Differential Localization of AMPA Glutamate Receptor Subunits in the Two Segments of the Globus Pallidus and the Substantia Nigra Pars Reticulata in the Squirrel Monkey

The subthalamic nucleus has long been known as the main source of glutamatergic afferents to the pallidum and the substantia nigra in primates. Recent findings showed that the excitatory effects induced by the subthalamic nucleus in pallidal cells are mediated through the activation of non-NMDA receptors in the rat. The objective of the present study was to analyse the distribution of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptor subunits in the external pallidum (GPe), the internal pallidum (GPi) and the substantia nigra pars reticulata (SNr) in squirrel monkeys ( Saimiri sciureus ). This was achieved by means of immunohistochemistry using antibodies raised against the GluR1 and the GluR2/3 subunits of the AMPA receptor. Our results show that all neuronal perikarya in GPe and GPi display immunoreactivity for GluR2/3 subunits whereas GluR1 is confined exclusively to cells in the GPe. The proportion of GluR1-immunoreactive neurons is not uniform throughout the rostrocaudal extent of GPe; in the rostral third all GPe cells display GluR1 immunoreactivity, whereas in the caudal third the proportion of GluR1-positive cells decreases to 50%. The intensity of GluR1 immunostaining associated with GPe cells is lower than that associated with neighbouring large-sized neurons in the nucleus basalis of Meynert. In contrast to GPi cells, the neurons in the SNr display immunoreactivity for both GluR1 and GluR2/3 subunits. In conclusion, our results provide the first evidence for a different distribution of the GluR1 subunit of the AMPA receptors in the two segments of the globus pallidus in monkeys. These findings imply that the control of the basal activity of GPe and GPi cells by the subthalamic nucleus is exerted via the activation of AMPA receptors composed of different subunits. These data reinforce the view that the two segments of the globus pallidus are different entities that possess their own functional characteristics in primates.     

Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism.

The goal of the study was to determine abnormalities in the spontaneous activity of globus pallidus neurons at the output of the basal ganglia, in cynomolgus monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In parkinsonian compared to intact monkeys, the mean spontaneous firing rate of the neurons of the internal segment of the globus pallidus (GPi) increased but that of the prevailing neuronal population in the external segment (GPe) inversely decreased. Correspondingly, the mean modal interval between spikes shortened, suggesting increased excitation, in both the GPi and GPe. However, the mean proportion of intervals longer than 100 ms increased in the GPe but remained unchanged in the GPi, suggesting increased inhibition only in the GPe. In the two populations, bursting activities and the mean variability of firing rate increased. Concurrently, a small and distinct neuronal population located in the GPe and another located at the periphery of both the GPi and GPe displayed minor changes, which were however different from those observed in the GPi and in the prevailing neuronal population of the GPe. The intensity of changes varied with time and severity of nigral lesion. In severe parkinsonism, the neuronal activity at the output of the basal ganglia (GPi) is excessive.     

Quantitative and ultrastructural study of serotonin innervation of the globus pallidus in squirrel monkeys

The present immunohistochemical study was aimed at characterizing the serotonin (5‐HT) innervation of the internal (GPi) and external (GPe) pallidal segments in the squirrel monkey (Saimiri sciureus) with an antibody against the 5‐HT transporter (SERT). At the light microscopic level, unbiased counts of SERT+ axon varicosities showed that the density of innervation is similar in the GPi (0.57 ± 0.03 × 10⁶ varicosities/mm³ of tissue) and the GPe (0.60 ± 0.04 × 10⁶), with the anterior half of both segments being more densely innervated than the posterior half. Dorsoventral and mediolateral decreasing gradients of SERT varicosities occur in both pallidal segments, but are statistically significant only in the GPi. The neuronal density being significantly greater in the GPe (3.41 ± 0.23 × 10³ neurons/mm³) than in the GPi (2.90 ± 0.11 × 103), the number of 5‐HT axon varicosities per pallidal neuron was found to be superior in the GPi (201 ± 27) than in the GPe (156 ± 26). At the electron microscopic level, SERT+ axon varicosities are comparable in size and vesicular content in GPi and GPe, where they establish mainly asynaptic contacts with unlabeled profiles. Less than 25% of SERT+ varicosities display a synaptic specialization, which is of the symmetrical or asymmetrical type and occurs exclusively on pallidal dendrites. No SERT+ axo‐axonic synapses are present, suggesting that 5‐HT exerts its well‐established modulatory action upon various pallidal afferents mainly through diffuse transmission, whereas its direct control of pallidal neurons results from both volumic and synaptic release of the transmitter.     

Neuronal globus pallidus activity in patients with generalised dystonia.

We studied 516 globus pallidus neurons in dystonic patients. The firing rate was analysed. We classified the burst activity into tonic, burst, and pause patterns. Mean +/- SD firing rates and tonicity score for internal globus pallidus (GPi) and external globus pallidus (GPe) were 54.6 +/- 28.6; 58.01 +/- 39.1 and 1.18 +/- 0.55; 0.95 +/- 0.43, respectively. Differences in percentage appearance of tonic, burst, or paused neurons were not statistically significant for GPi versus GPe. GPi firing features in dystonic patients were closely similar to those of GPe. This could suggest that the abnormally patterned output from GPi would not result from increased differential inhibitory/excitatory input arising from the direct/indirect pathway but rather be transmitted from GPe, striatum, or either centromedian nucleus.     

Cortical evoked potentials from pallidal stimulation in patients with primary generalized dystonia

Deep brain stimulation (DBS) of globus pallidus internus (GPi) has emerged as an effective treatment for primary generalized dystonia. However, the physiological mechanisms of improvement are not fully understood. Cortical activity in response to pallidal stimulation was recorded in 6 patients with primary generalized dystonia >6 months after bilateral GPi DBS. Scalp electroencephalogram was recorded using 60 surface electrodes during 10 Hz bipolar pallidal DBS at each electrode contact pair. Anatomical position of the electrode contacts in relation to the GPi, medial medullary lamina and globus pallidus externus (GPe) was determined from the postoperative stereotactic MRI. In all six patients an evoked potential (EP) was observed with average onset latency of 10.9 ms ± 0.77, peak latency 26.6 ms ± 1.6, distributed mainly over the ipsilateral hemisphere, maximal centrally. The mean amplitude of this potential was larger with stimulation in posteroventral GPi than in GPe (3.36 μV vs. 0.50 μV, P < 0.0001). The EP was absent in one patient‐side, ipsilateral to a previous thalamotomy. Low frequency GPi stimulation produces an EP distributed centrally over the ipsilateral hemisphere. The latency and distribution of the EP are consistent with stimulation of pallidothalamic neurons projecting to the sensorimotor cortex. Because the EP is larger and more consistently present with stimulation of posteroventral GPi than GPe, it may provide a physiological tool to identify contacts within the optimal surgical target. © 2007 Movement Disorder Society     

A case of adult onset pure pallidal degeneration. II. Analysis of neurotransmitter markers, with special reference to the termination of pallidothalamic tract in human brain.

We analyzed neurotransmitter markers in a brain of a very rare case of pathologically confirmed adult-onset pure pallidal degeneration (PPD) as compared with 16 controls. Neurotransmitter concentrations are significantly altered in the globus pallidus (GP), subthalamic nucleus (ST) and the thalamic nuclei. Concentrations of gamma-aminobutyric acid (GABA) in the external segment (GPe) and internal segment (GPi) of GP and ST are decreased to 62, 45 and 55% of the control mean, respectively. Concentrations of glutamic acid are increased in GPi (144%) and ST (134%). Choline acetyltransferase (ChAT) activities are increased in GPe (232%), GPi (218%), ST (161%), and ventroanterior (VA, 210%) and ventrolateral nucleus (VL, 193%) of the thalamus. Noradrenaline (NA) concentrations in GPe and GPi are 56 and 43% of the control mean, respectively. Dopaminergic and serotonergic systems show no remarkable change. The grid microdissection analysis demonstrates a patchy GABA distribution in the thalamus of 3 controls, whereas a small GABA-rich area in the ventro-oral nucleus (VO) according to the atlas of Hopf disappears in adult onset PPD. These results strongly suggest that (1) GP GABAergic neurons are selectively degenerated and striatopallidal GABAergic nerve terminals are hypoactive; (2) ChAT activities in GP, ST, VA and VL are increased; (3) the subthalamopallidal glutamatergic system is not hypoactive; (4) activity of the noradrenergic system in GP is decreased; and that (5) VO in the thalamus specifically receives GABAergic nerve terminals from GP in human brain.     

Lrrk2 localization in the primate basal ganglia and thalamus: A light and electron microscopic analysis in monkeys

The Leucine Rich Repeat Kinase-2 (LRRK2) gene is a common mutation target in Parkinson's disease (PD), but the cellular mechanisms by which such mutations underlie the pathophysiology of PD remain poorly understood. Thus, to better characterize the neuronal target sites of LRRK2 mutations in the primate brain, we studied the cellular and ultrastructural localization of Lrrk2 immunoreactivity in the monkey basal ganglia. As previously described, the monkey striatum was the most enriched basal ganglia structure in Lrrk2 labeling. Both projection neurons and parvalbumin-containing GABAergic interneurons displayed Lrrk2 immunoreactivity. At the electron microscopic level, striatal Lrrk2 labeling was associated predominantly with dendritic shafts and subsets of putative glutamatergic axon terminals. At the pallidal level, moderate cellular Lrrk2 immunostaining was found in the external globus pallidus (GPe), while neurons in the internal globus pallidus (GPi) were devoid of Lrrk2 immunoreactivity. Strong labeling was associated with cholinergic neurons in the nucleus basalis of Meynert. Midbrain dopaminergic neurons in the primate substantia nigra pars compacta (SNc) and ventral tegmental area harbored a significant level of Lrrk2 labeling, while neurons in the subthalamic nucleus were lightly immunostained. Most thalamic nuclei were enriched in Lrrk2 immunoreactivity, except for the centromedian nucleus that was completely devoid of labeling. Thus, Lrrk2 protein is widely distributed in the monkey basal ganglia, suggesting that gene mutations in PD may result in multifarious pathophysiological effects that could impact various target sites in the functional circuitry of the primate basal ganglia.     

Anesthesia reduces discharge rates in the human pallidum without changing the discharge rate ratio between pallidal segments

Classical rate models of basal ganglia circuitry associate discharge rate of the globus pallidus external and internal segments (GPe, GPi respectively) solely with dopaminergic state and predict an inverse ratio between the discharge rates of the two pallidal segments. In contrast, the effects of other rate modulators such as general anesthesia (GA) on this ratio have been ignored. To respond to this need, we recorded the neuronal activity in the GPe and GPi in awake and anesthetized human patients with dystonia (57 and 53 trajectories respectively) and in awake patients with Parkinson's disease (PD, 16 trajectories) undergoing deep brain stimulation procedures. This triad enabled us to dissociate pallidal discharge ratio from general discharge modulation. An automatic offline spike detection and isolation quality system was used to select 1560 highly isolated units for analysis. The mean discharge rate in the GPi of awake PD patients was dramatically higher than in awake dystonia patients although the firing rate in the GPe was similar. Firing rates in dystonic patients under anesthesia were lower in both nuclei. Surprisingly, in all three groups, GPe firing rates were correlated with firing rates in the ipsilateral GPi. Thus, the firing rate ratio of ipsilateral GPi/GPe pairs was similar in awake and anesthetized patients with dystonia and significantly higher in PD. We suggest that pallidal activity is modulated by at least two independent processes: dopaminergic state which changes the GPi/GPe firing rate ratio, and anesthesia which modulates firing rates in both pallidal nuclei without changing the ratio between their firing rates.     

Relationship between neurokinin-1 receptor and substance P in the striatum: light and electron microscopic immunohistochemical study in the rat

The synaptic relationship between substance P (SP) and its receptor, i.e., neurokinin-1 receptor (NK1R), was examined in the striatum of the rat by confocal laser-scanning microscopy and electron microscopy. For confocal laser-scanning microscopy, triple-immunofluorescence histochemistry was performed to label NK1R, SP, and vesicular acetylcholine transporter (a specific marker for cholinergic neurons). In electron microscopic double-immunolabeling study, immunoreactivity for NK1R was detected with the silver-intensified gold method, while immunoreactivity for SP was detected with peroxidase immunohistochemistry. Simultaneous immunolabeling of NK1R and SP revealed significant mismatch at the synaptic level: although some SP-immunopositive axon terminals were in synaptic contact with NK1R-immunopositive sites of plasma membrane, NK1R-immunoreactivity was observed at both synaptic and non-synaptic sites of plasma membrane. Thus, SP released from the sites remote from NK1Rs might diffuse in the extracellular fluid to act, as a paracrine neurotransmitter, on NK1Rs distant from its releasing site. SP neurotransmission in the striatum might occur not only synaptically but also extrasynaptically. The SP-NK1R system might constitute an association system within the striatum.     

Substance P excites globus pallidus neurons in vivo

Substance P is a member of the neurokinin family. Previous studies have reported the existence of substance P and its high-affinity receptor, neurokinin-1 receptor, in globus pallidus. Employing in vivo extracellular recording combined with behavioural tests, the effects of substance P in globus pallidus of rats were studied. Micropressure ejection of the selective neurokinin-1 receptor agonist [Sar9,Met(O2)11] substance P increased the spontaneous firing rate of pallidal neurons in a concentration-dependent manner, with increases of 27.3% at 0.01, 33.4% at 0.03, 45.5% at 0.1, 38.4% at 0.3 and 36.4% at 1.0 mm. The selective neurokinin-1 receptor antagonist SR140333B prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. In behaving rats, we observed the postural effects of neurokinin-1 receptor activation in the globus pallidus. Consistent with electrophysiological results, unilateral microinjection of [Sar9,Met(O2)11] substance P (0.1 mm) led to a SR140333B-sensitive contralateral deflection in the presence of systemic haloperidol administration. Combining electrophysiological and behavioural findings, we concluded that substance P produces excitatory effects on globus pallidus neurons via neurokinin-1 receptors.     

Analysis of neuronal connections in the basal ganglia]

Morphological features indicating occurrence of two types of extrasynaptic chemical transmission were observed within rat basal ganglia. (1) Striatonigral neurons containing substance P (SP) sent many axon collaterals equipped with axonal varicosities to the striatum: the varicosities displayed synaptophysin-like immunoreactivity (-LI). However, only 15% of the varicosities appeared to be in close contact with structures showing SP receptor (SPR)-LI. Many of axon terminals of striatonigral neurons were confirmed electron microscopically not to be in synaptic contact with SPR-like immunoreactive structures within the striatum. SP released from the varicosities might, at least partly, diffuse to reach SPR at distance from the release sites. (2) Immunoreactivities for metabotropic glutamate receptors (mGluRs) 4 a, 7 a, 7 b and 8 were in axon terminals within the globus pallidus (external segment of the globus pallidus in primates). The immunoreactivities disappeared after destruction of the striatum, but not after destruction of the subthalamic nucleus. The immunoreactivity for mGluR 7 a was confirmed electron microscopically to be within axon terminals showing glutamic acid decarboxylase-LI. Glutamate released from glutamatergic subthalamopallidal neurons might partly spilled over from the synaptic sites to reach mGluRs on "nearby" axon terminals of GABAergic striatopallidal neurons. Functional significance of thalamostriatal and corticosubthalamic fibers was also discussed.     

Localization and pharmacological modulation of GABA-B receptors in the globus pallidus of parkinsonian monkeys

Changes in GABAergic transmission in the external and internal segments of the globus pallidus (GPe and GPi) contribute to the pathophysiology of the basal ganglia network in Parkinson's disease. Because GABA-B receptors are involved in the modulation of GABAergic transmission in GPe and GPi, it is possible that changes in the functions or localization of these receptors contribute to the changes in GABAergic transmission. To further examine this question, we investigated the anatomical localization of GABA-B receptors and the electrophysiologic effects of microinjections of GABA-B receptor ligands in GPe and GPi of MPTP-treated (parkinsonian) monkeys. We found that the pattern of cellular and ultrastructural localization of the GABA-BR1 subunit of the GABA-B receptor in GPe and GPi was not significantly altered in parkinsonian monkeys. However, the magnitude of reduction in firing rate of GPe and GPi neurons produced by microinjections of the GABA-B receptor agonist baclofen was larger in MPTP-treated animals than in normal monkeys. Injections of the GABA-B receptor antagonist CGP55845A were more effective in reducing the firing rate of GPi neurons in parkinsonian monkeys than in normal animals. In addition, the injections of baclofen in GPe and GPi, or of CGP55845A in GPi lead to a significant increase in the proportion of spikes in rebound bursts in parkinsonian animals, but not in normal monkeys. Thus, despite the lack of changes in the localization of GABA-BR1 subunits in the pallidum, GABA-B receptor-mediated effects are altered in the GPe and GPi of parkinsonian monkeys. These changes in GABA-B receptor function may contribute to bursting activities in the parkinsonian state.     

Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site-directed antisense gene therapy.

The levels of mRNA encoding the two isoforms of glutamic acid decarboxylase (GAD(65) and GAD(67)) were measured throughout the pallidal complex in normal and acutely (i.e., 1 month duration) and chronically (i.e., 5 years duration) parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated monkeys as well as in monkeys exposed to MPTP but asymptomatic for parkinsonism. GAD(65) mRNA labeling was modestly increased in the mid/caudal internal globus pallidus (GPi) but not in the external globus pallidus (GPe) in parkinsonian monkeys, compared with normal and asymptomatic monkeys. GAD(67) mRNA expression was highly increased in the mid/caudal GPi, and modestly increased in the GPe in parkinsonian monkeys compared with normal and asymptomatic animals. Infusion of GAD(67) antisense oligodeoxynucleotides bilaterally into the GPi resulted in a transient reversal of akinesia and bradykinesia that was not produced by infusion of missense oligodeoxynucleotides. These data emphasize the role of GAD enzyme (particularly GAD(67)) and GABA in the GPi for the expression of parkinsonian motor signs and suggest that selective manipulation of GABAergic neurotransmission in the GPi may have therapeutic potential for treating parkinsonism.     

Plasticity of the nigropallidal pathway in Parkinson's disease

The degeneration of nigrostriatal dopamine neurons in early Parkinson's disease (PD) is compensated in part by increased transmitter turnover in surviving neurons of the pathway. In this (18)F-dopa positron emission tomography study, we demonstrate compensatory changes in PD in another midbrain dopamine projection to the basal ganglia, the nigropallidal projection to the internal segment of the globus pallidus (GPi). Increased (18)F-dopa uptake in the GPi is seen in early PD which then is lost in advanced PD. Our early PD cases show an absence of significant clinical progression in the face of a continuing loss of nigrostriatal projections. This indicates a compensatory neuronal plasticity that we now show to involve the nigropallidal dopamine pathway to the GPi but not to the external segment of the globus pallidus (GPe). Enhanced function of the dopamine projection to the GPi serves, we propose, to maintain a more normal pattern of pallidal output to ventral thalamus and motor cortex in early PD, whereas loss of this adaptive pathway in advanced disease may be a pivotal step in the progression of the disease.     

External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinson's disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD.     

Single-axon tracing study of neurons of the external segment of the globus pallidus in primate

Axonal projections arising from the external segment of the globus pallidus (GPe) in cynomolgus monkeys (Macaca fascicularis) were mapped after labeling small pools (5-15 cells) of neurons with biotinylated dextran amine. Seventy-six single axons were reconstructed from serial sagittal sections with a camera lucida. The majority of labeled GPe cells displayed long, aspiny, and poorly branched dendrites that arborized mostly along the sagittal plane, whereas others showed dendrites radiating in all directions. Numerous GPe axons emitted short, intranuclear collaterals that arborized close to their parent cell body. Based on their axonal targets, four distinct types of GPe projection neurons have been identified: 1) neurons that project to the internal segment of the globus pallidus (GPi), the subthalamic nucleus (STN), and the substantia nigra, pars reticulata (SNr; 13.2%); 2) neurons that target the GPi and the STN (18.4%); 3) neurons that project to the STN and the SNr (52.6%); and 4) neurons that target the striatum (15.8%). Labeled GPe axons displayed large varicosities that often were closely apposed to the somata and proximal dendrites of STN, GPi, and SNr neurons. At striatal levels, however, GPe axons displayed small axonal varicosities that did not form perineuronal nets. These results suggest that the GPe is an important integrative locus in primate basal ganglia. This nucleus harbors several subtypes of projection neurons that are endowed with a highly patterned set of collaterals. This organization allows single GPe neurons to exert a multifarious effect not only on the STN, which is the claimed GPe target, but also on the two major output structures of the basal ganglia, the SNr and the GPi.     

Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys

The internal segment of the globus pallidus (GPi) receives motor-related cortical signals mainly through the striatum, the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). The GPi sends its outputs outside the basal ganglia and plays a key role in motor control. Extracellular unit recordings were performed in awake monkeys to explore how glutamatergic STN inputs and GABAergic striatal and GPe inputs control spontaneous activity and how these inputs contribute to motor cortex stimulation-induced responses of GPi neurons. The typical responses of GPi neurons to cortical stimulation consisted of an early excitation, an inhibition and a late excitation. Local applications of the NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid and/or the AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide in the vicinity of recorded GPi neurons reduced the firing rate, and abolished or attenuated both early and late excitations following cortical stimulation. Local application of the GABA_A receptor antagonist gabazine increased the firing rate, induced oscillatory firings and diminished the cortically induced inhibition. Muscimol or gabazine injection into the STN or GPe also altered the firing rate, and attenuated the late excitation of GPi neurons. The gabazine injection into the STN occasionally induced dyskinesia with significantly decreased GPi activity. These data suggest that the early and late excitations are glutamatergic and induced by the cortico-STN-GPi and cortico-striato-GPe-STN-GPi pathways, respectively. The inhibition is GABAergic and induced by the cortico-striato-GPi pathway. In addition, these inputs are the main factors governing the spontaneous activity of GPi neurons.     

Neuronal activity in the globus pallidus of multiple system atrophy patients.

The pathophysiological changes in neural activity that characterize multiple system atrophy (MSA) are largely unknown. We recorded the activity of pallidal neurons in 3 patients with clinical and radiological features of MSA who underwent unilateral microelectrode-guided pallidotomy for disabling parkinsonism. Findings in these patients were compared with 4 control patients with a clinical diagnosis of Parkinson's disease (PD). The position, firing rates, and firing patterns of single neurons in the pallidal complex were analyzed in both MSA and PD patients. The mean spontaneous firing rate of neurons in the internal segment of the globus pallidus internus (GPii) was significantly lower in MSA than in PD patients. There were no significant differences between MSA and PD patients, however, in firing rates of neurons in the external globus pallidus (GPe) or in the external segment of GPi (GPie). In addition, no significant differences in firing pattern were found between MSA and PD patients. In conclusion, this study has shown that firing rates of neurons in GPii but not in GPie and GPe are different in MSA patients compared with that in PD patients, a finding that may reflect the poor clinical results of pallidotomy reported in patients with MSA.     

Met-enkephalin immunoreactivity in the basal ganglia in Parkinson's disease and striatonigral degeneration

This study concerns the expression of Met-enkephalin (MEnk) in the striatum and the external segment of the globus pallidus proper (GPe) in normal controls, idiopathic Parkinson's disease (PD), and striatonigral degeneration (SND). For this purpose, we developed a sensitive immunoperoxidase technique to visualize MEnk-positive patches in routinely prepared formalin-fixed paraffin-embedded striatal tissues. In comparison with normal controls, MEnk-positive patches and pallidal MEnk-positive axon terminals were strongly present in patients with PD, showing characteristic distribution patterns. By comparison, in SND patients, there was striking diminution of MEnk staining in the putamen and ventrolateral portion of the GPe, while MEnk patches were persistent in the caudate nucleus.