Basal Ganglia Output Nuclei Research Articles

Evidence for the importance of basal ganglia output nuclei in semantic event sequencing: An fMRI study

Semantic event sequencing is the ability to plan ahead and order meaningful events chronologically. To investigate the neural systems supporting this ability, an fMRI picture sequencing task was developed. Participants sequenced a series of four pictures presented in random order based on the temporal relationship among them. A control object discrimination task was designed to be comparable to the sequencing task regarding semantic, visuospatial, and motor processing requirements but without sequencing demands. fMRI revealed significant activation in the dorsolateral prefrontal cortex and globus pallidus internal part in the picture sequencing task compared with the control task. The findings suggest that circuits involving the frontal lobe and basal ganglia output nuclei are important for picture sequencing and more generally for the sequential ordering of events. This is consistent with the idea that the basal ganglia output nuclei are critical not only for motor but also for high-level cognitive function, including behaviors involving meaningful information. We suggest that the interaction between the frontal lobes and basal ganglia output nuclei in semantic event sequencing can be generalized to include the sequential ordering of behaviors in which the selective updating of neural representations is the key computation.

Rhythmic bursting in the cortico-subthalamo-pallidal network during spontaneous genetically determined spike and wave discharges.

Absence seizures are characterized by impairment of consciousness associated with bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect paroxysmal oscillations in thalamocortical networks. Although recent studies suggest that the subthalamic nucleus (STN) provides an endogenous control system that influences the occurrence of absence seizures, the mechanisms of propagation of cortical epileptic discharges in the STN have never been explored. The present study provides the first description of the electrophysiological activity in the cortico-subthalamo-pallidal network during absence seizures in the genetic absence epilepsy rats from Strasbourg, a well established model of absence epilepsy. In corticosubthalamic neurons, the SWDs were associated with repetitive suprathreshold depolarizations correlated with EEG spikes. These cortical paroxysms were reflected in the STN by synchronized, rhythmic, high-frequency bursts of action potentials. Intracellular recordings revealed that the intraburst pattern in STN neurons was sculpted by an early depolarizing synaptic potential, followed by a short hyperpolarization and a rebound of excitation. The rhythmic hyperpolarizations in STN neurons during SWDs likely originate from a subpopulation of pallidal neurons exhibiting rhythmic bursting temporally correlated with the EEG spikes. The repetitive discharges in STN neurons accompanying absence seizures might convey powerful excitation to basal ganglia output nuclei and, consequently, may participate in the control of thalamocortical SWDs.

Neuronal activity in the primate substantia nigra pars reticulata during the performance of simple and memory-guided elbow movements.

The basal ganglia participate in motor functions and are implicated in the pathophysiology of movement disorders. It has been shown in primates that the activity of many neurons in one of the basal ganglia output nuclei, the internal segment of the globus pallidus, changes with active or passive movements. The involvement of the second major output nucleus, the substantia nigra pars reticulata (SNr), in movement is less well established. In this study, the electrophysiologic activity of SNr neurons was studied in two awake Rhesus monkeys while the animals were examined and while they performed elbow movements in two different motor tasks (n = 261 cells). Responses to examination were uncommon and subtle. Twenty-one percent of neurons responded to the target step in a step tracking task, mostly with anticipatory responses, although some cells showed directional, movement-related activity. In a delayed-response task, 17% of cells showed anticipatory activity to an instruction cue preceding the target jump, 11% responded directly to the cue, and 11% showed long-lasting postcue activity. Movement-related responses were seen in 21% in this task. Reward responses occurred in 10% of neurons. Responses to more than one event were common. The results demonstrate that few neurons in the SNr respond directly to passive or active movements, but a large proportion shows responses that may be related to memory, attention, or movement preparation. While internal pallidal segment neurons may be preferentially concerned with controlling elemental movement parameters, neurons in the SNr may be more involved in higher motor functions or nonmotor aspects of behavior.

Delayed onset of huntington′s disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors

Huntington's disease (HD) is a late onset progressive genetic disorder characterised by motor dysfunction, personality changes, dementia and premature death. The disease is caused by an unstable expanded trinucleotide (CAG) repeat encoding a polyglutamine stretch in the IT15 gene for huntingtin, a protein of unknown function. Transgenic mice expressing exon one of the human HD gene with an expanded polyglutamine region develop many features of human HD. Exposure of these mice to an “enriched” environment delays the onset of motor disorders and slows disease progression [Nature 404 (2000) 721]. We have compared the levels of receptor binding of a range of basal ganglia neurotransmitter receptors believed to be important in HD, in normal mice and R6/1 transgenic HD mice housed in either enriched or standard laboratory environments. HD mice housed in a normal environment show a loss of cannabinoid CB1 and dopamine D1 and D2 receptors in the striatum and the corresponding output nuclei of the basal ganglia. HD mice exposed to an enriched environment show equivalent loss of D1 and D2 receptors as their “non-enriched” counterparts; in contrast, the “enriched” mice show significantly less depletion of CB1 receptors. In the brains of humans diagnosed with HD cannabinoid CB1 receptors are selectively lost from the basal ganglia output nuclei prior to the development of other identifiable neuropathology [Neuroscience 97 (2000) 505]. Our results therefore show that an enhanced environment slows the rate of loss of one of the first identifiable neurochemical deficits of HD. This suggests that delaying the loss of CB1 receptors, either by environmental stimulation or pharmacologically, may be beneficial in delaying disease progression in HD patients.

Nigral GABAergic inhibition upon cholinergic neurons in the rat pedunculopontine tegmental nucleus.

We investigated, in a midbrain parasagittal slice preparation of Wistar rats (postnatal day 9-17), the synaptic inhibition of neurons in the pedunculopontine tegmental nucleus (PPN), which was mediated by gamma (gamma)-amino-butyric acid (GABA). Whole-cell patch-clamp recording was used, in combination with a single-cell reverse transcription-polymerase chain reaction amplification technique, to record synaptic potentials and to identify the phenotype of the recorded PPN neuron. In the presence of the ionotropic glutamate receptor antagonists, 6-cyano-2, 3-dihydroxy-7-nitro-quinoxaline-2, 3, dione, and dl-2-amino-5-phosphonovaleric acid, single electrical stimuli were applied to the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei. Stimulation of the SNr evoked inhibitory postsynaptic potentials (IPSPs) in 73 of the 104 neurons in the PPN. The IPSPs were abolished with a GABAA receptor antagonist, bicuculline. Inhibitory postsynaptic currents of the neurons were reversed in polarity at approximately -93.5 mV, which was close to the value of the equilibrium potential for chloride ions of -88.4 mV. Single-cell reverse transcription-polymerase chain reactions revealed that approximately 30% (9/32) of the PPN neurons that received inhibition from the SNr expressed detectable levels of choline acetyltransferase mRNA. These findings show that output from the SNr regulates the activity of cholinergic PPN neurons through GABAA receptors.

Aged F344 rats exhibit altered electrophysiological activity in locomotor-unrelated but not locomotor-related striatal neurons

Multi-wire electrode arrays were chronically implanted and striatal electrophysiological activity was recorded in young (4–9 months) versus aged (24–29 months) Fischer 344 (F344) rats in order to determine whether locomotor-related striatal neurons exhibit age-related changes in electrophysiological activity during freely-moving conditions. Individual neurons were classified as locomotor-related if they exhibited significant differences in their firing rates between periods of locomotion versus periods of non-movement. While the activity of locomotor-related striatal neurons did not differ between young and aged rats, neurons that were not related to locomotion exhibited significantly greater activity in the aged rats during both periods of non-movement and bouts of locomotion. These results suggest that in the aged striatum, increased activity of nonlocomotor-related neurons may contribute to hypokinesia through their influence on basal ganglia output nuclei. Such studies may aid in the understanding of movement disorders seen in aging and Parkinson’s disease.

Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions.

A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.

Nigrostriatal lesion and dopamine agonists affect firing patterns of rodent entopeduncular nucleus neurons.

Altered activity of the entopeduncular nucleus, the rodent homologue of the globus pallidus internal segment in primates, is thought to mediate behavioral consequences of midbrain dopamine depletion in rodents. Few studies, however, have examined dopaminergic modulation of spiking activity in this nucleus. This study characterizes changes in entopeduncular neuronal activity after nigrostriatal dopaminergic lesion and the effects of systemic treatment with selective D(1) (SKF 38393) and D(2) (quinpirole) agonists in lesioned rats. Extracellular single-unit recordings were performed in awake immobilized rats, either in neurologically intact animals (n = 42) or in animals that had received unilateral 6-hydroxydopamine infusion into the medial forebrain bundle several weeks previously (n = 35). Nigrostriatal lesion altered baseline activity of entopeduncular neurons in several ways. Interspike interval distributions had significantly decreased modes and significantly increased coefficient of variation, skewness and kurtosis; yet interspike interval mean (the inverse of firing rate) was not affected. Also, spectral analysis of autocorrelograms indicated that lesion significantly reduced the incidence of regular-spiking neurons and increased the incidence of neurons with 4-18 Hz oscillations. Dopamine agonist treatment reversed some lesion-induced effects: quinpirole reversed changes in interspike interval distribution mode and coefficient of variation, while combined quinpirole and SKF 38393 blocked the appearance of 4-18 Hz oscillations. However, no agonist treatment normalized all aspects of entopeduncular activity. Additionally, inhibition of firing rates by D(1) or combined D(1)/D(2) receptor activation indicated that dopamine agonists affected the overall level of entopeduncular activity in a manner similar to that found in the substantia nigra pars reticulata and globus pallidus internal segment after dopamine neuron lesion. These data demonstrate that lesion of the nigrostriatal tract leads to modifications of several aspects of firing pattern in the rodent entopeduncular nucleus and so expand on similar findings in the rodent substantia nigra pars reticulata and in the globus pallidus internal segment in humans and nonhuman primates. The results support the view that dysfunction in the basal ganglia after midbrain dopamine neuron loss relates more consistently to abnormal activity patterns than to net changes in firing rate in the basal ganglia output nuclei, while overall decreases in firing rate in these structures may play a more important role in adverse motor reactions to dopamine agonist treatments.

Regional decreases in NK-3, but not NK-1 tachykinin receptor binding in dystonic hamster ( dtsz) brains

Although the pathophysiology of primary dystonias is currently unknown, it is thought to involve changes in the basal ganglia–thalamus–cortex circuit, particularly activity imbalances between direct and indirect striatal pathways. Substance P, a member of the tachykinin family of neuropeptides, is a major component in the direct pathway from striatum to basal ganglia output nuclei. In the present study quantitative autoradiography was used to examine changes in neurokinin-1 (NK-1) and neurokinin-3 (NK-3) receptors in mutant dystonic hamsters ( dt sz), a well characterized model of paroxysmal dystonia. NK-1 receptors were labeled in 10 dystonic brains and 10 age-matched controls with 3 nM [ 3H]-[Sar 9, Met(O 2) 11]-SP. NK-3 binding sites were labeled in adjacent sections with 2.5 nM [ 3H]senktide. NK-1 binding was found to be unaltered in 27 brain areas examined. In contrast, NK-3 binding was significantly reduced in layers 4 and 5 of the prefrontal (−46%), anterior cingulate (−42%) and parietal (−45%) cortices, ventromedial thalamus (−42%) and substantia nigra pars compacta (−36%) in dystonic brains compared to controls. The latter effects may be particularly relevant in view of evidence that activation of NK-3 receptors on dopaminergic neurons in the substantia nigra pars compacta can increase nigrostriatal dopaminergic activity. Since previous studies indicated that a reduced basal ganglia output in mutant hamsters is based on an overactivity of the direct pathway which also innervates substantia nigra pars compacta neurons, the decreased NK-3 binding could be related to a receptor down-regulation. The present finding of decreased NK-3 receptor density in the substantia nigra pars compacta, thalamic and cortical areas substantiates the hypothesis that disturbances of the basal ganglia–thalamus–cortex circuit play a critical role in the pathogenesis of paroxysmal dystonia.

The parafascicular thalamic complex and basal ganglia circuitry: further complexity to the basal ganglia model

This work is focused on the study of neuronal circuits arising from the rodent caudal intralaminar nuclei and their presumed role on basal ganglia function. Emphasis was placed on the analysis of the architecture of thalamostriatal and thalamo-subthalamic projections in albino rats. Our major interest was to elucidate whether thalamic inputs were related to projection neurons or local circuit neurons within targeted structures (striatum and subthalamic nucleus). Projections coming from the parafascicular nucleus (PF) to the striatum displayed a patchy organization throughout the matrix compartment. These patches are composed by dense terminal axonal arborizations, often containing striatal neurons projecting to the entopeduncular nucleus (ENT) (medial globus pallidus in primates) and neurons projecting to the substantia nigra reticulata (SNR). The thalamostriatal projections under scrutiny were also seen to be in register with all the major classes of striatal interneurons (nitrergic neurons, neurons containing the calcium binding protein parvalbumin (PV) and cholinergic interneurons). Subthalamic neurons projecting to the ENT are the presumed postsynaptic target for fibers coming from the sensorimotor part (dorsolateral) of the PF. In summary, glutamatergic axons arising from the PF might exert a dual control of the striatal output, either by directly exciting striatal projection neurons or indirectly by means of a previous synaptic contact onto an striatal interneuron which in turn modulates the activity of projection neurons. Furthermore, thalamic inputs can also gain access to basal ganglia output nuclei via subthalamo-pallidal projecting neurons, neurons receiving glutamatergic thalamo-subthalamic projections. Thus, activation of either circuit has an opposite physiological effect on the basal ganglia output nucleus. Taken together, these data suggest that the PF may influence neuronal activity in the direct and indirect circuits and could be considered as an additional component of the basal ganglia motor loops.

Amphetamine inhibits behavior-related neuronal responses in substantia nigra pars reticulata of rats working for sucrose reinforcement

Changes in activity of basal ganglia neurons, especially those in the striatum, are thought to underlie the characteristic behavioral patterns produced by d-amphetamine (AMPH). To study the role of the substantia nigra pars reticulata (SNr), a major basal ganglia output nucleus, we recorded from SNr neurons before and after a behaviorally activating dose of AMPH (0.5 mg/kg) in rats trained to nosepoke for sucrose reinforcement. Before AMPH, task-related behaviors were associated primarily with increases or both increases and decreases in SNr firing. Although these same behavior-related patterns persisted after AMPH, their relative magnitude was significantly attenuated. Units unresponsive during task events were unaffected by AMPH. Thus, rather than change the overall level of SNr firing, a behaviorally active dose of AMPH exerts context-dependent effects on the activity of SNr neurons.

Dendritic Arborizations of the Rat Substantia Nigra Pars Reticulata Neurons: Spatial Organization and Relation to the Lamellar Compartmentation of Striato-Nigral Projections

The cerebral cortex provides a major source of inputs to the basal ganglia. As has been well documented, the topography of corticostriatal projections subdivides the striatum into a mosaic of functionally distinct sectors. How information flow from these striatal sectors remains segregated or not within basal ganglia output nuclei has to be established. Electrophysiologically identified neurons of the rat substantia nigra pars reticulata were labeled by juxtacellular injection of Neurobiotin, and the spatial organization of their dendritic arborizations was analyzed in relation to the projection fields of individual striatal sectors. Thirty-nine nigral neurons located in the projection territory of the distinct striatal sensorimotor sectors were reconstructed. The data show that the dendritic arborizations of nigral neurons conform to the geometry of striato-nigral projections. Like striatal projections, the arborizations formed a series of curved laminas enveloping a dorsolaterally located core. Although dendritic fields of the neurons lying in the laminae were flat, those located in the core were spherical or cylindrical, thereby conforming to the shape of the striatal projection fields. This remarkable alignment between the dendritic arborizations of nigral neurons and the projection fields from individual striatal districts supports the concept of a parallel architecture of the striato-nigral circuits. However, pars reticulata neurons usually extend part of their dendrites within adjacent striatal projection fields, thereby ensuring a continuum between channels. The extension of the dendritic arborizations within the striatal projection fields suggests that nigral neurons integrate the information that is relevant for the completion of the specific motor behavior they control.

Cortical Slow Oscillatory Activity Is Reflected in the Membrane Potential and Spike Trains of Striatal Neurons in Rats with Chronic Nigrostriatal Lesions

Neurons in the basal ganglia output nuclei display rhythmic burst firing after chronic nigrostriatal lesions. The thalamocortical network is a strong endogenous generator of oscillatory activity, and the striatum receives a massive projection from the cerebral cortex. Actually, the membrane potential of striatal projection neurons displays periodic shifts between a very negative resting potential (down state) and depolarizing plateaus (up states) during which they can fire action potentials. We hypothesized that an increased excitability of striatal neurons may allow transmission of cortical slow rhythms through the striatum to the remaining basal ganglia in experimental parkinsonism. In vivo intracellular recordings revealed that striatal projection neurons from rats with chronic nigrostriatal lesions had a more depolarized membrane potential during both the down and up states and an increased firing probability during the up events. Furthermore, lesioned rats had significantly fewer silent neurons than control rats. Simultaneous recordings of the frontal electrocorticogram and membrane potential of striatal projection neurons revealed that the signals were oscillating synchronously in the frequency range 0.4-2 Hz, both in control rats and rats with chronic nigrostriatal lesions. Spreading of the slow cortical rhythm is limited by the very low firing probability of control rat neurons, but a slow oscillation is well reflected in spike trains of approximately 60% of lesioned rat neurons. These findings provide in vivo evidence for a role of dopamine in controlling the flow of cortical activity through the striatum and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.

Activation of metabotropic glutamate receptor 1 inhibits glutamatergic transmission in the substantia nigra pars reticulata

The substantia nigra pars reticulata is a primary output nucleus of the basal ganglia motor circuit and is controlled by a fine balance between excitatory and inhibitory inputs. The major excitatory input to GABAergic neurons in the substantia nigra arises from glutamatergic neurons in the subthalamic nucleus, whereas inhibitory inputs arise mainly from the striatum and the globus pallidus. Anatomical studies revealed that metabotropic glutamate receptors (mGluRs) are highly expressed throughout the basal ganglia. Interestingly, mRNA for group I mGluRs are abundant in neurons of the subthalamic nucleus and the substantia nigra pars reticulata. Thus, it is possible that group I mGluRs play a role in the modulation of glutamatergic synaptic transmission at excitatory subthalamonigral synapses. To test this hypothesis, we investigated the effects of group I mGluR activation on excitatory synaptic transmission in putative GABAergic neurons in the substantia nigra pars reticulata using the whole cell patch clamp recording approach in slices of rat midbrain. We report that activation of group I mGluRs by the selective agonist ( R, S)-3,5-dihydroxyphenylglycine (100 μM) decreases synaptic transmission at excitatory synapses in the substantia nigra pars reticulata. This effect is selectively mediated by presynaptic activation of the group I mGluR subtype, mGluR1. Consistent with these data, electron microscopic immunocytochemical studies demonstrate the localization of mGluR1a at presynaptic sites in the rat substantia nigra pars reticulata. From this finding that group I mGluRs modulate the major excitatory inputs to GABAergic neurons in the substantia nigra pars reticulata we suggest that these receptors may play an important role in basal ganglia functions. Studying this effect, therefore, provides new insights into the modulatory role of glutamate in basal ganglia output nuclei in physiological and pathophysiological conditions.

Intrastriatal injection of D 1 or D 2 dopamine agonists affects glucose utilization in both the direct and indirect pathways of the rat basal ganglia

Two distinct pathways are thought to connect the striatum to the basal ganglia output nuclei: a direct pathway, originating from neurons bearing dopamine, D 1 receptors and an indirect pathway, originating from neurons expressing D 2 receptors. It has been recently suggested, however, that dopamine receptor sub-types may co-localize and co-operate in the striatum. We sought to verify the functional segregation of the two pathways by measuring cerebral glucose utilization following intrastriatal injection of selective D 1 (SKF 38393), D 2 (quinpirole), or non-selective indirect (amphetamine) and direct (apomorphine) dopamine agonists, in freely-moving rats. All drugs – regardless of receptor selectivity – reduced glucose utilization in nuclei of both the direct and indirect pathways, thus lending further support to the existence of a functional co-operation of striatal D 1 and D 2 receptors.

Anatomy, physiology, and pharmacology of the basal ganglia

The basal ganglia consist of five interconnected nuclei in the basal forebrain that influence cortical control of voluntary movement. Synaptic information travels through the basal ganglia using distinct pathways from the input structure, the striatum, to the output nuclei, the substantia nigra pars reticulata and the globus pallidus internal segment. The activity of the striatal output pathways is influenced by glutamatergic input from the cerebral cortex, dopaminergic input from the substantia nigra pars compacta, and cholinergic interneurons. Since the basal ganglia output nuclei tonically inhibit the motor nuclei of the thalamus, the basal ganglia facilitate motor activity by disinhibiting the thalamus.

Activation of groups I or III metabotropic glutamate receptors inhibits excitatory transmission in the rat subthalamic nucleus

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN.

Subthalamic nucleus lesions reduce low frequency oscillatory firing of substantia nigra pars reticulata neurons in a rat model of Parkinson’s disease

Single unit recordings performed in animal models of Parkinson’s disease revealed that output nuclei neurons display modifications in firing pattern and firing rate, which are supposed to give rise to the clinical manifestations of the illness. We examined the activity pattern of single units from the substantia nigra pars reticulata, the main output nuclei of the rodent basal ganglia, in urethane-anesthetized control and 6-hydroxydopamine-lesioned rats (a widespread model of Parkinson’s disease). We further studied the effect of a subthalamic nucleus lesion in both experimental groups. Subthalamic nucleus lesion produces behavioral improvement in animal models of Parkinson’s disease, and was expected to reverse the changes induced by 6-hydroxydopamine lesions. A meticulous statistical investigation, which included a non-biased classification of the recorded units by means of cluster analysis, allowed us to identify a low frequency oscillation of firing rate (∼0.9 Hz) occurring in ∼35% of the units recorded from 6-hydroxydopamine-lesioned rats, as the main feature differentiating 6-hydroxydopamine-lesioned and control rats. Subthalamic nucleus lesions significantly reduced the proportion of oscillatory units in 6-hydroxydopamine-lesioned rats. However, the population of nigral units recorded from rats bearing both lesions still differed significantly from control units. These results suggest that oscillatory activity in the basal ganglia output nuclei may be related to some clinical features of parkinsonism, and suggest a putative mechanism through which therapeutic interventions aimed at modifying subthalamic nucleus function produce clinical benefit in Parkinson’s disease.

Activation of Metabotropic Glutamate Receptor 5 Has Direct Excitatory Effects and Potentiates NMDA Receptor Currents in Neurons of the Subthalamic Nucleus

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.

Deficit of Striatal Parvalbumin-Reactive GABAergic Interneurons and Decreased Basal Ganglia Output in a Genetic Rodent Model of Idiopathic Paroxysmal Dystonia

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.