Search

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson's disease (PD) argue that the GPe is important in motor control. Parvalbumin-positive (PV+) neurons and Npas1+neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV+neurons and Npas1+neurons promoted and suppressed locomotion, respectively. Moreover, PV+neurons and Npas1+neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV+neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe–STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.SIGNIFICANCE STATEMENTThe external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurologic diseases, such as Parkinson's disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor function/dysfunction. This was in part because of the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson's disease.

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+projection was dramatically strengthened. AsDLSdSPN-Npas1+projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opposing output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum ((DMS)dSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum ((DLS)dSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1(+) neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1(+) projection was dramatically strengthened. As (DLS)dSPN-Npas1(+) projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson's disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states. SIGNIFICANCE STATEMENT In the classic basal ganglia model, the striatum is described as a divergent structure: it controls motor and adaptive functions through two segregated, opposing output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal subpathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this subpathway undergoes changes in a Parkinson's disease model. In particular, our results suggest that the increase in strength of this subpathway contributes to the slowness or reduced movements observed in Parkinson's disease.

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson’s disease (PD) argue that the GPe is important in motor control. PV+ neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV+ neurons and Npas1+ neurons promoted and suppressed locomotion, respectively. Moreover, PV+ neurons and Npas1+ neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV+ neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.Significance StatementThe external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurological diseases, such as Parkinson’s disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor (dys)function. This was in part due to the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson’s disease.

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson's disease (PD) argue that the GPe is important in motor control. Parvalbumin-positive (PV(+)) neurons and Npas1(+) neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV(+) neurons and Npas1(+) neurons promoted and suppressed locomotion, respectively. Moreover, PV(+) neurons and Npas1(+) neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV(+) neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe–STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies. SIGNIFICANCE STATEMENT The external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurologic diseases, such as Parkinson's disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor function/dysfunction. This was in part because of the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson's disease.

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2(+) neurons and ChAT(+) neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6(+) neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6(+) population. Neurons that arise from the Dbx1(+) lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1(+)-Nkx2.1(+) neurons represent the principal noncholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further show that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on preexisting tools. Although spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes: PV(+) neurons and Npas1(+) neurons. SIGNIFICANCE STATEMENT The poor understanding of the neuronal composition in the external globus pallidus (GPe) undermines our ability to interrogate its precise behavioral and disease involvements. In this study, 12 different genetic crosses were used, hundreds of neurons were electrophysiologically characterized, and >100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1(+)–Nkx2.1(+) neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+neurons and ChAT+neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+population. Neurons that arise from the Dbx1+lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes—i.e., PV+neurons and Npas1+neurons.Significance statementThe poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

Compelling evidence demonstrates that the external globus pallidus (GPe) plays a key role in processing sensorimotor information. An anatomical projection from the GPe to the dorsal striatum has been described for decades. However, the cellular target and functional impact of this projection remain unknown. Using cell-specific transgenic mice, modern monosynaptic tracing techniques, and optogenetics-based mapping, we discovered that GPe neurons provide inhibitory inputs to direct and indirect pathway striatal projection neurons (SPNs). Our results indicate that the GPe input to SPNs arises primarily from Npas1-expressing neurons and is strengthened in a chronic Parkinson's disease (PD) model. Alterations of the GPe-SPN input in a PD model argue for the critical position of this connection in regulating basal ganglia motor output and PD symptomatology. Finally, chemogenetic activation of Npas1-expressing GPe neurons suppresses motor output, arguing that strengthening of the GPe-SPN connection is maladaptive and may underlie the hypokinetic symptoms in PD.SIGNIFICANCE STATEMENTAn anatomical projection from the pallidum to the striatum has been described for decades, but little is known about its connectivity pattern. The authors dissect the presynaptic and postsynaptic neurons involved in this projection, and show its cell-specific remodeling and strengthening in parkinsonian mice. Chemogenetic activation of Npas1+pallidal neurons that give rise to the principal pallidostriatal projection increases the time that the mice spend motionless. This argues that maladaptive strengthening of this connection underlies the paucity of volitional movements, which is a hallmark of Parkinson's disease.

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex-nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex-NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson9s disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the markers parvalbumin and Npas1. Our study provides evidence that parvalbumin and Npas1 neurons have different topologies within the basal ganglia.

Midbrain dopamine (DA) neurons have diverse functions that can in part be explained by their heterogeneity. Although molecularly distinct subtypes of DA neurons have been identified by single-cell gene expression profiling, fundamental features such as their projection patterns have not been elucidated. Progress in this regard has been hindered by the lack of genetic tools for studying DA neuron subtypes. Here we develop intersectional genetic labeling strategies, based on combinatorial gene expression, to map the projections of molecularly defined DA neuron subtypes. We reveal distinct genetically defined dopaminergic pathways arising from the substantia nigra pars compacta and from the ventral tegmental area that innervate specific regions of the caudate putamen, nucleus accumbens and amygdala. Together, the genetic toolbox and DA neuron subtype projections presented here constitute a resource that will accelerate the investigation of this clinically significant neurotransmitter system.

The globus pallidus plays an important role in movement regulation. Morphological studies have revealed GABA(B) receptor expression in the globus pallidus. To investigate the behavioral and electrophysiological effects of pallidal GABA(B) receptors on haloperidol-induced akinesia, microinjection and extracellular recordings were performed in the present study. Unilateral microinjection of GABA(B) receptor agonist, baclofen, into globus pallidus produced ipsilateral dystonic posturing in haloperidol-induced akinesia rats. However, microinjection of GABA(B) receptor antagonist, CGP55845, induced contralateral dystonic posturing, suggesting the tonic activity of pallidal GABAergic neurotransmission. Micro-pressure ejection of baclofen into globus pallidus decreased the spontaneous firing of pallidal neurons. Furthermore, local administration of CGP55845 alone induced a weak but consistent increase in the frequency of pallidal firing. The presence of CGP55845 prevented baclofen-induced effects completely. From the present in vivo findings it may be concluded that pallidal GABA(B) receptors may contribute to the therapy of parkinsonian akinesia by modulating the activity of globus pallidus.

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(02)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(02)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(02)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.

The globus pallidus plays a critical role in movement regulation. Morphological study has indicated that the globus pallidus receives neurotensinergic innervation from the striatum. The present study investigated the effects of activating neurotensin receptor in globus pallidus. In vivo single unit electrophysiological recordings showed that micro-pressure ejection of neurotensin into the globus pallidus increased spontaneous firing of pallidal neurons. The excitatory effect of neurotensin could be mimicked by the C-terminal fragment, neurotensin (8-13), but not by the N-terminal fragment, neurotensin (1-8). Local administration of both the non-selective neurotensin receptor antagonist, SR142948A, and the selective neurotensin type-1 receptor antagonist, SR48692, blocked the excitatory effect induced by neurotensin. In the behaving rats, we observed the postural effects of neurotensin in the globus pallidus. Unilateral microinjection of neurotensin into the globus pallidus induced a SR48692-sensitive contralateral dystonic posturing in the presence of systemic haloperidol administration, which could be accounted for by the electrophysiological effect of neurotensin in increasing the firing rate of pallidal neurons. Our in vivo electrophysiological and behavioral findings suggest that pallidal neurotensin receptor plays a role in the basal ganglia motor circuit by mediating an excitation of spontaneous activity in the globus pallidus.

Mice carrying bacterial artificial chromosome (BAC) transgenes have become important tools for neuroscientists, providing a powerful means of dissecting complex neural circuits in the brain. Recently, it was reported that one popular line of these mice--mice possessing a BAC transgene with a D(2) dopamine receptor (Drd2) promoter construct coupled to an enhanced green fluorescent protein (eGFP) reporter--had abnormal striatal gene expression, physiology, and motor behavior. Unlike most of the work using BAC mice, this interesting study relied upon mice backcrossed on the outbred Swiss Webster (SW) strain that were homozygous for the Drd2-eGFP BAC transgene. The experiments reported here were conducted to determine whether mouse strain or zygosity was a factor in the reported abnormalities. As reported, SW mice were very sensitive to transgene expression. However, in more commonly used inbred strains of mice (C57BL/6, FVB/N) that were hemizygous for the transgene, the Drd2-eGFP BAC transgene did not alter striatal gene expression, physiology, or motor behavior. Thus, the use of inbred strains of mice that are hemizygous for the Drd2 BAC transgene provides a reliable tool for studying basal ganglia function.

PURPOSE: To investigate dendritic changes of retinal ganglion cells (RGCs) and the rate of dendritic shrinkage after retinal ischemia induced by acute elevation of intraocular pressure (IOP). METHODS: After elevating the IOP to 110 mm Hg for 30, 60, 90, and 120 minutes, a confocal scanning laser ophthalmoscope (CSLO) was used to serially image the retinas of the Thy-1 YFP transgenic mice in vivo for 1 to 3 months. Dendritic and axonal arborizations of 52 RGCs were visualized and followed longitudinally. Dendritic field, dendritic branching complexity (modified Sholl analysis), axonal diameter, and cell body area were measured. A total of 426 longitudinal measurements of dendritic field and dendritic complexity were analyzed for estimation of rate of change with linear mixed modeling. RESULTS: There were no morphologic changes of RGCs after 30 (n = 12) or 60 (n = 12) minutes of ischemia. After 90 minutes of ischemia (n = 19), 78.9% of RGCs showed progressive loss of dendrites, axon, and cell body, 5.3% had only mild reduction of branching complexity and shrinkage of dendritic field whereas 15.8% showed no morphologic changes. All RGCs lost dendritic and axonal arborizations after 120 minutes of ischemia (n = 9). The rates of reduction of dendritic field were 11.7% per day (95% confidence interval, 5.0%-18.4% per day) after 90 minutes, and 15.1% per day (10.3%-19.9% per day) after 120 minutes of ischemia. CONCLUSIONS: RGCs demonstrated dendritic shrinkage after 90 to 120 minutes, but not after 30 to 60 minutes of ischemia. In vivo imaging of dendritic changes could provide a sensitive approach to measure the rate of dendritic shrinkage after acute IOP elevation.

Based on mixture model, the numerical simulation of solid-liquid two-phase flow in a double channel pump (Specific speed ns = 81) was carried out. The effects of particle diameter, particle volume fraction and flow rate on solid volume concentration distribution, relative velocity distribution and abrasion characteristics were studied. The results reveal that in the impeller, more particles concentrate at the nut of the shaft end and the edge of the impeller outlet. So those regions are worn seriously. The abrasive types are sliding wear on the impeller outlet edge and impact wear on the nut respectively. In the wall of the volute, the concentrated areas of particles move round the anticlockwise direction when the mixture flow rate is larger. The reason is the mixture velocity is larger as the flow rate increases, and meanwhile the centrifugal force and gravity force are invariable. So the particles move round the impeller rotational direction consequently. In the volute, particles concentrate on the tongue and wall region, especially on the sections I, II, V and VII. So the areas are easily worn out. The abrasive type is the heavy sliding wear in the volute wall. Numerical simulation results are consistent with the actual situation. It follows that the calculating method is feasible.

The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O2)11] substance P (SM-SP) at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

Substance P is an important neurotransmitter or neuromodulator in central nervous system. Morphological studies have revealed the existence of substance P and its high affinity receptor, neurokinin-1 receptor , in globus pallidus. The expression of neurokinin-1 receptor in external globus pallidus has been reported to be decreased or unchanged in parkinsonian patients. To further investigate the effects of pallidal neurokinin-1 receptor in Parkinson's disease , an in vivo extracellular recording in 6-hydroxydopamine parkinsonian rats was performed. Micro-pressure ejection of selective neurokinin-1 receptor agonist, [Sar9,Met(O2)11] substance P (0.1 mM), increased the spontaneous firing rate of pallidal neurons by 9.1% on the lesioned side, which was significantly weaker than that on the unlesioned side (20.7%), and that in normal rats (30.0%). The selective neurokinin-1 receptor antagonist , SR140333B, prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. Based on the action of substance P in globus pallidus of parkinsonian rats we hypothesize that the activity of neurokinin-1 receptors in globus pallidus may be decreased under parkinsonian state. This finding may provide a rationale for further investigations into the potential of pallidal substance P system in the treatment of Parkinson's disease .

Summary The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity of the striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.