Neural signatures of hyperdirect pathway activity in Parkinson's disease.

Parkinson's disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21-30 Hz) but not low (13-21 Hz) beta frequency range correlated with 'hyperdirect pathway' fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.

The Insertion of Electrodes in the Brain for Electrophysiological Recording or Chronic Stimulation Is Not Associated With Any Biochemically Detectable Neuronal Injury.

OBJECTIVE: The aim of this study was to evaluate the degree of brain tissue injury that could be potentially induced by the introduction of a) microrecording electrodes, b) macrostimulation electrodes, or c) chronic stimulation electrodes. We aimed to evaluate whether the use of five simultaneous microrecording tracks is associated with any brain injury not detectable by conventional imaging such as CT or MRI. MATERIALS AND METHODS: The study included 61 patients who underwent surgery for implantation of 121 DBS leads. In all cases, five simultaneous tracts were utilized for microelectrode recordings. All patients underwent measurements of serum S-100b at specific time points as follows: a) prior to the operation, and b) intraoperatively at specific stages of the procedure: 1) after opening the burr hole, 2) after the insertion of microrecording electrodes, 3) during macrostimulation, 4) at the end of the operation, and 5) on the first postoperative day. RESULTS: The levels of serum S-100B protein remained within the normal range during the entire period of investigation in all patients with the exception of two cases. In both patients, the procedure was complicated by intraparenchymal hemorrhage visible in neuro-imaging. The first patient developed a small intraparenchymal hemorrhage, visible on the postoperative MRI, with no neurological deficit. The second patient experienced a focal epileptic seizure after the insertion of the right DBS chronic lead and the postoperative CT scan revealed a right frontal lobe hemorrhage. CONCLUSION: These results strongly indicate that the insertion of either multiple recording electrodes or the implantation of chronic electrodes in DBS does not increase the risk of brain hemorrhage or of other intracranial complications, and furthermore it does not cause any biochemically detectable brain tissue damage.

Direct visualization of the subthalamic nucleus and its iron distribution using high-resolution susceptibility mapping.

Histological studies have shown a relatively high iron concentration in the subthalamic nucleus (STN). T2- and T2*-weighted sequences have previously been used to visualize the STN in vivo. The phase information of gradient-echo images reflects the magnetic tissue properties more directly, e.g., iron is more paramagnetic than water. Unfortunately, phase images suffer from non-local effects and orientation dependency. The goal of this study is to delineate the STN more precisely using susceptibility maps, calculated from phase images, which directly index magnetic tissue properties while removing the non-local effects and orientation dependency. Use of 7T MRI enables high spatial resolution with good signal to noise ratio (SNR). Eight healthy subjects were scanned at 7T using a high-resolution 3D gradient-echo sequence. Susceptibility maps were calculated from phase data using a thresholding Fourier approach and a regularization approach using spatial priors. The susceptibility maps clearly distinguish the STN from the adjacent substantia nigra (SN). Their susceptibilities are quantitatively different (0.06 and 0.1 ppm for the STN and SN, respectively). These maps allowed the STN, SN, and the red nucleus to be manually segmented, thus providing 3D visualization of their boundaries. In sum, the STN can be more clearly distinguished from adjacent structures in susceptibility maps than in T2*-weighted images or phase images.

Change of extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in epileptic rats.

OBJECTIVE: To study the neurochemical change during high-frequency stimulation of the subthalamic nucleus in epileptic rats. METHODS: Two animal groups - 12 rats with epilepsy induced by the systemic administration of kainic acid and 12 normal rats - were used. Concentric bipolar electrodes were stereotaxically implanted in the unilateral subthalamic nucleus (STN), stimulated by high frequencies of 130 and 260 Hz in each group. The microdialysis probes were unilaterally lowered into the globus pallidus (GP) and the substantia nigra pars reticulata (SNr). The concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in dialysate samples were determined by high-performance liquid chromatography. RESULTS: Electrical stimulation of the STN induced increases in GABA content in the SNr of each group, while GABA remained stable in the GP. The extracellular GABA level in the epileptic group was significantly higher than that of the normal group. In addition, the frequency of 130 Hz provoked the maximum increase in Glu contents both in the GP and SNr, whereas 260 Hz had less effect. CONCLUSIONS: This study demonstrates the neurochemical modifications in STN targets during electrical STN stimulation and shows that different frequencies of high-frequency stimulation have different effects on the neurotransmitters.

Different tau pathology pattern in two clinical phenotypes of progressive supranuclear palsy.

BACKGROUND: The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Recent clinicopathological studies showed much more severe and more widespread tau pathology in Richardson's syndrome (RS), clinically manifest by early onset, falls, supranuclear gaze palsy, dementia and shorter disease duration than in atypical PSP-parkinsonism (PSP-P) often mimicking Parkinson's disease, in which tau pathology is relatively restricted to substantia nigra, subthalamic nucleus and internal globus pallidus. OBJECTIVE: To perform a comparative clinicopathological study of 30 autopsy-proven cases of PSP. METHODS: Retrospective assessment of major clinical signs in 18 patients referred to as RS and 12 PSP-P, and semiquantitative assessment of the severity and distribution pattern of tau pathology in both phenotypes using routine stains and immunohistochemistry. RESULTS: RS (61% males) and PSP-P (33% males) showed significant differences in clinical symptomatology and course (RS mean duration 4.2 years, PSP-P 13.8 years) and significant differences in histopathology: widespread tau pathology and related multisystem degeneration in RS and more restricted lesions in PSP-P, which, however, were not only involving predominantly the subthalamo-nigral-pallidal system. Cortical tau pathology in both groups was usually restricted to limbic areas, and neocortical Alzheimer-type pathology was only seen in very old or demented PSP patients. CONCLUSIONS: The present study confirmed the recently reported existence of two distinct clinical phenotypes in patients with pathologically proven PSP-P and RS, showing significant differences in severity and distribution of tau pathology, the latter more severe and more widely distributed than in PSP-P.

Localization and expression of group I metabotropic glutamate receptors in the mouse striatum, globus pallidus, and subthalamic nucleus: regulatory effects of MPTP treatment and constitutive Homer deletion.

Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, regulate activity in the globus pallidus (GP) and subthalamic nucleus (STN). To test whether the localization of group I mGluRs is altered in parkinsonism, we used immunoelectron microscopy to analyze the subcellular and subsynaptic distribution of mGluR1a and mGluR5 in GP and STN of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Homer1 and Homer2 knock-out mice were used to assess the role of Homer in MPTP-induced redistribution of group I mGluRs. We also examined the effects of MPTP on the expression levels of group I mGluRs and Homer proteins in GP and striatum. MPTP treatment significantly reduced the expression levels of H1a and mGluR1a in striatum but not in GP. Although light microscopy did not reveal noticeable effects of MPTP treatment on the distribution of group I mGluRs and Homer proteins in GP and STN, specific changes in the ultrastructural localization of mGluR1a were found in MPTP-treated normal and Homer knock-out mice. An increase in the expression of presynaptic axonal and terminal mGluR1a labeling and an increased level of mGluR1a immunoreactivity in the postsynaptic specialization of putative GABAergic synapses were among the most significant effects induced by dopamine depletion. However, neither of these changes was found for mGluR5, which, in contrast, displayed complex regulatory alterations in its subsynaptic distribution in response to Homer deletion and MPTP lesion. Thus, nigrostriatal dopaminergic lesion and Homer deletion lead to changes in the trafficking of group I mGluRs in vivo that are specific to receptor subtypes and brain areas.

Involvement of sensorimotor, limbic, and associative basal ganglia domains in L-3,4-dihydroxyphenylalanine-induced dyskinesia.

Dyskinesia represents a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson's disease. Such motor manifestations are attributed to pathological activity in the motor parts of basal ganglia. However, because consistent funneling of information takes place between the sensorimotor, limbic, and associative basal ganglia domains, we hypothesized that nonmotor domains play a role in these manifestations. Here we report the changes in 2-deoxyglucose (2-DG) accumulation in the sensorimotor, limbic, and associative domains of basal ganglia and thalamic nuclei of four groups of nonhuman primates: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa and exhibiting overt dyskinesia. Although nondyskinetic animals display a rather normalized metabolic activity, dyskinetic animals are distinguished by significant changes in 2-DG accumulation in limbic- and associative-related structures and not simply in sensorimotor-related ones, suggesting that dyskinesia is linked to a pathological processing of limbic and cognitive information. We propose that these metabolic changes reflect the underlying neural mechanisms of not simply motor dyskinesias but also affective, motivational, and cognitive disorders associated with long-term exposure to L-dopa.

[Lesions in the pars compacta substantiae nigra and the subthalamic nucleus modify the density of muscarinic receptors in different nuclei of the basal ganglia]. / La lesión de la sustancia negra pars compacta y del núcleo subtalámico modifica la densidad de receptores muscarínicos en distintos núcleos de los ganglios basales.

INTRODUCTION: Several studies that has focused to the dopaminergic transmission in the basal ganglia in parkinsonian condition, but only a few article has taking into account the imbalance between dopaminergic and cholinergic transmission. OBJECTIVE: To evaluate the muscarinic cholinergic receptors density in SNc and PPN in the 6-OHDA model. MATERIALS AND METHODS: Were organized five experimental groups in correspondence to the place of the lesion: I. Non treated rats, II. 6-OHDA lesion in SNc, III. 6-OHDA lesion in SNc + quinolinic acid lesion in NST, IV. Sham operated rats, V. Quinolinic acid in STN. Were obtained coronal sections of 20 microm thickness of SNc and PPN from rats and in these sections was evaluated the muscarinic receptors density through autoradiographic technique with [3H]quinuclidinylbenzilate (QNB) (1.23 nM). The muscarinic antagonist atropine (1 microM) was utilized as non-specific union. The density was evaluated in both hemispheres and the density optical was converted in fentomolas/mg of tissue with base to values obtained from tritium standards. RESULTS: Significant diminution of the muscarinic receptors density was found in the SNc ipsilateral to the 6-OHDA lesion from experimental groups II (t=2.76; p<0.05) and III (t=4.06; p<0.05). In the group V, was seen a significant increase of muscarinic receptor density in the SNc ipsilateral to the 6-OHDA lesion. The comparison between experimental groups evidenced significant differences among them (F=13.13; p<0.001) with a significant decrease in the density from SNc of groups II and III and significant increase in the density from SNc of group V in comparison of the others groups. In relation to PPN, muscarinic receptors density from right PPN ipsilateral to the 6-OHDA lesion, shown significant differences (F=3.93; p<0.01) between the experimental groups with a significant increase of this variable in the group II. CONCLUSIONS: These results signal a modification of cholinergic activity after 6-OHDA lesion. The changes in the muscarinic receptors populations located in SNc and PPN could be part of different compensatory mechanisms to attempt ameliorate the imbalance between dopaminergic and cholinergic transmission that it was installed after denervation of nigrostriatal forebrain bundle. The excitotoxic lesion of STN impose a new adjust mechanism for cell from PPN, which could be expressed in the changes of muscarinic cholinergic receptors population at the level of SNc.

Neurochemical mechanisms induced by high frequency stimulation of the subthalamic nucleus: increase of extracellular striatal glutamate and GABA in normal and hemiparkinsonian rats.

High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial effects in patients suffering from severe parkinsonism, but the mechanisms underlying these clinical results remain to be clarified. To date, very little is known concerning the effects of STN-HFS on neurochemical transmission in the different basal ganglia nuclei and in particular the striatum. This study examines the effects of STN-HFS in intact and hemiparkinsonian rats on extracellular striatal glutamate (Glu) and GABA levels by means of intracerebral microdialysis. Unilateral STN-HFS was found to induce a significant bilateral increase of striatal Glu and GABA both in intact and in dopamine-lesioned animals. In intact rats, these increases were reversed by local administration of the D1 antagonist SCH 23390, but were potentiated by the D2 antagonist sulpiride. Potentiation was also observed after local administration of both D1 and D2 antagonists whose amplitude was similar to that measured in hemiparkinsonian rats. These data furnish the first evidence that STN-HFS influences striatal amino-acid transmission and that this influence is modulated by dopamine. They provide evidence that the effects of STN-HFS are not only restricted to the direct STN targets, but also involve adaptive changes within other structures of the basal ganglia circuitry.

Haloperidol-induced alteration in the physiological actions of group I mGlus in the subthalamic nucleus and the substantia nigra pars reticulata.

Excitatory glutamatergic inputs to the subthalamic nucleus (STN), and subthalamic afferents to the substantia nigra pars reticulata (SNr) are believed to play a key role in the pathophysiology of Parkinson's disease (PD). Previously, we have shown that activation of the group I mGlus in the STN and SNr induces a direct depolarization of the neurons in these nuclei. Surprisingly, although both group I mGlus were present in the STN and SNr, mGlu5 alone mediated the DHPG-induced depolarization of the STN, and mGlu1 alone mediated the DHPG-induced depolarization of the SNr. We now report that both mGlu1 and mGlu5 are coexpressed in the same cells in both of these brain regions, and that both receptors play a role in mediating the DHPG-induced increase in intracellular calcium. Furthermore, we demonstrate that the induction of an acute PD-like state using a 16 h haloperidol treatment produces an alteration in the coupling of the group I receptors, such that post-haloperidol, DHPG-induced depolarizations are mediated by both mGlu1 and mGlu5 in the STN and SNr. Therefore, the pharmacology of the group I mGlu-mediated depolarization depends on the state of the system, and alterations in receptor coupling may be evident in pathological states such as PD.

High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.

Co-localization of AMPA-type glutamate receptor immunoreactivity in neurons of the rat subthalamic nucleus.

In order to determine the precise cellular localization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptor subunit immunoreactivity in the rat subthalamic nucleus, single and double immunofluorescence was performed. Intense level of GluR1, GluR2, GluR2/3 and GluR4 immunoreactivity was found in almost all neurons of the subthalamic nucleus. By double immunofluorescence, the subthalamic neurons in the same sections that displayed a strong immunoreactivity for GluR1 were found to display a robust GluR2 immunoreactivity and the subthalamic neurons that displayed GluR2 immunoreactivity were also found to express GluR4 immunoreactivity. The present results thus demonstrate that individual neurons of the subthalamic nucleus are likely to co-express GluR1 and GluR2, and GluR2 and GluR4 immunoreactivity. The native AMPA channels in the subthalamic neurons may, therefore, be composed of heteromeric subunits. The present results provide information of the neuroanatomical localization of AMPA receptor subunits in neurons of the subthalamic nucleus. The localization of AMPA receptor subunits may be related to functional characteristics of AMPA channels in the subthalamic neurons.

Characterization of Ca(2+) channels in rat subthalamic nucleus neurons.

The subthalamic nucleus (STN) plays a key role in motor control. Although previous studies have suggested that Ca(2+) conductances may be involved in regulating the activity of STN neurons, Ca(2+) channels in this region have not yet been characterized. We have therefore investigated the subtypes and functional characteristics of Ca(2+) conductances in STN neurons, in both acutely isolated and slice preparations. Acutely isolated STN cells were identified by retrograde filling with the fluorescent dye, Fluoro-Gold. In acutely isolated STN neurons, Cd(2+)-sensitive, depolarization-activated Ba(2+) currents were observed in all cells studied. The current-voltage relationship and current kinetics were characteristic of high-voltage-activated Ca(2+) channels. The steady-state voltage-dependent activation curves and inactivation curves could both be fitted with a single Boltzmann function. Currents evoked with a prolonged pulse, however, inactivated with multiple time constants, suggesting either the presence of more than one Ca(2+) channel subtype or multiple inactivation processes with a single channel type in STN neurons. Experiments using organic Ca(2+) channel blockers revealed that on average, 21% of the current was nifedipine sensitive, 52% was sensitive to omega-conotoxin GVIA, 16% was blocked by a high concentration of omega-agatoxin IVA (200 nM), and the remainder of the current (9%) was resistant to the co-application of all blockers. These currents had similar voltage dependencies, but the nifedipine-sensitive current and the resistant current activated at slightly lower voltages. omega-Agatoxin IVA at 20 nM was ineffective in blocking the current. Together, the above results suggest that acutely isolated STN neurons have all subtypes of high-voltage-activated Ca(2+) channels except for P-type, but have no low-voltage-activated channels. Although acutely isolated neurons provide a good preparation for whole cell voltage-clamp study, dendritic processes are lost during dissociation. To gain information on Ca(2+) channels in dendrites, we thus studied Ca(2+) channels of STN neurons in a slice preparation, focusing on low-voltage-activated channels. In current-clamp recordings, a slow spike was always observed following termination of an injected hyperpolarizing current. The slow spike occurred at resting membrane potentials and was sensitive to micromolar concentrations of Ni(2+), suggesting that it is a low-threshold Ca(2+) spike. Together, our results suggest that STN neurons express low-voltage-activated Ca(2+) channels and several high-voltage-activated subtypes. Our results also suggest the possibility that the low-voltage-activated channels have a preferential distribution to the dendritic processes.

The indirect basal ganglia pathway in dopamine D(2) receptor-deficient mice.

Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D(2) dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D(2) dopamine receptor gene allowed us to test these predictions. When compared with their congenic N(5) wild-type siblings, mice lacking D(2) receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D(2) receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D(2) receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D(2) receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D(2) receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D(2) receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways.

Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson's disease patients.

The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.

Increased behavioral response to dopaminergic stimulation of the subthalamic nucleus after nigrostriatal lesions.

Local infusions of the nonselective dopaminergic agonist apomorphine into the subthalamic nucleus of rats has been shown to elicit orofacial dyskinesia which can be blocked by D1 but not D2 receptor antagonists. In the present study, we show that the selective D1 agonist A77636 also induces orofacial dyskinesia when injected into the subthalamic nucleus of awake rats, thus confirming a role for D1 receptors in this effect. We also examined the dyskinesia induced by intrasubthalamic injections of apomorphine in rats with an ipsilateral lesion of the nigrostriatal pathway. The orofacial response to local administration of apomorphine (1.0 microg) into the subthalamic nucleus was markedly increased in the lesioned rats. As in control rats, the enhanced behavioral response seen in lesioned rats was blocked by peripheral administration of D1 antagonists. Although D1 receptor binding autoradiography revealed no difference in D1 receptor binding in the subthalamic nucleus on the side of the lesion compared to controls, D1 binding was higher in the subthalamic nucleus on the side of the lesion compared to the contralateral side. The increased behavioral response observed after unilateral dopamine denervation suggests that the subthalamic nucleus is tonically regulated by dopaminergic projections from the substantia nigra. Furthermore, the data suggest that subthalamic D1 receptors may be involved in the development of dyskinesia induced by dopaminergic drugs.

Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study.

Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and are classified into three groups (I, II and III) based on amino acid sequence identity, effector systems and pharmacological profile. Previous results have shown that unilateral stimulation of metabotropic glutamate receptors in the subthalamic nucleus with the non-subtype-selective metabotropic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthalamic nucleus. This suggests that metabotropic glutamate receptor stimulation results in altered subthalamic nucleus activity with consequent altered basal ganglia activity on the injected side. We sought to determine the metabotropic glutamate receptor subtype(s) involved and the functional neuroanatomy underlying the rotational behavior. Unilateral intrasubthalamic nucleus injection of group II or group III metabotropic glutamate receptor agonists induced contralateral rotation. In addition to producing rotation, group II and group III metabotropic glutamate receptor agonists induce toxicity in the subthalamic nucleus and overlying thalamus. Following group II or group III subthalamic nucleus metabotropic glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examination of [14C]2-deoxyglucose uptake suggests that the alterations in basal ganglia activity are different following group II versus group III metabotropic glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic glutamate receptors induces rotation by increasing subthalamic nucleus activity. These results suggest that group II metabotropic glutamate receptor antagonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease.

A light and electron microscopic study of GAT-1 in the monkey basal ganglia.

The distribution of the GABA transporter GAT-1 was studied by immunocytochemistry and electron microscopy in the monkey basal ganglia. Dense staining was observed in the globus pallidus externa and interna, intermediate in the subthalamic nucleus, and substantia nigra, and light staining in the caudate nucleus and putamen. Staining was observed in axon terminals, but not cell bodies. Electron microscopy showed that the GAT-1 positive axon terminals formed symmetrical synapses, suggesting that they were the terminals of GABAergic neurons. Comparison of areas high in GAT-1 protein with that of GABA showed a good correlation between the density in neuropil staining for GAT-1, and that of GABA.