Sodium <Emphasis Type="Italic">P</Emphasis>-Aminosalicylic Acid Improved Manganese-Induced Learning and Memory Dysfunction via Restoring the Ultrastructural Alterations and γ-Aminobutyric Acid Metabolism Imbalance in the Basal Ganglia

Excessive intake of manganese (Mn) may cause neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has been used successfully in the treatment of Mn-induced neurotoxicity. The γ-aminobutyric acid (GABA) is related with learning and memory abilities. However, the mechanism of PAS-Na on improving Mn-induced behavioral deficits is unclear. The current study was aimed to investigate the effects of PAS-Na on Mn-induced behavioral deficits and the involvement of ultrastructural alterations and γ-aminobutyric acid (GABA) metabolism in the basal ganglia of rats. Sprague-Dawley rats received daily intraperitoneally injections of 15 mg/kg MnCl₂.4H₂O, 5d/week for 4 weeks, followed by a daily back subcutaneously (sc.) dose of PAS-Na (100 and 200 mg/kg), 5 days/week for another 3 or 6 weeks. Mn exposure for 4 weeks and then ceased Mn exposure for 3 or 6 weeks impaired spatial learning and memory abilities, and these effects were long-lasting. Moreover, Mn exposure caused ultrastructural alterations in the basal ganglia expressed as swollen neuronal with increasing the electron density in the protrusions structure and fuzzed the interval of neuropil, together with swollen, focal hyperplasia, and hypertrophy of astrocytes. Additionally, the results also indicated that Mn exposure increased Glu/GABA values as by feedback loops controlling GAT-1, GABA_A mRNA and GABA_A protein expression through decreasing GABA transporter 1(GAT-1) and GABA A receptor (GABA_A) mRNA expression, and increasing GABA_A protein expression in the basal ganglia. But Mn exposure had no effects on GAT-1 protein expression. PAS-Na treatment for 3 or 6 weeks effectively restored the above-mentioned adverse effects induced by Mn. In conclusion, these findings suggest the involvement of GABA metabolism and ultrastructural alterations of basal ganglia in PAS-Na’s protective effects on the spatial learning and memory abilities.     

Localization and physiological roles of metabotropic glutamate receptors in the direct and indirect pathways of the basal ganglia

Summary.  Our current understanding of the circuitry of the basal ganglia, and the pathophysiology of Parkinson's disease has led to major breakthroughs in the treatment of this debilitating movement disorder. Unfortunately, there are significant problems with the currently available pharmacological therapies that focus on dopamine replacement or dopaminergic agonists. Because of this, much effort has been focused on developing novel targets for the treatment of Parkinson's disease. The metabotropic glutamate receptors are a family of G-protein coupled receptors activated by glutamate. These receptors are differentially distributed throughout the basal ganglia in a manner suggesting that they may provide novel targets for the treatment of movement disorders. In this review we summarize anatomical and physiological data from our work and the work of other laboratories describing the distribution and physiological roles of metabotropic glutamate receptors in the basal ganglia with emphasis on possible therapeutic targets. Received July 2, 2001 Accepted August, 6, 2001 Published online June 26, 2002     

Metabotropic glutamate receptors in the basal ganglia motor circuit

In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.     

Striatal information signaling and integration in globus pallidus: timing matters

Advances in research on globus pallidus (GP) suggest that this 'long thought to be' relay in the 'indirect pathway' plays a unique and critical role in basal ganglia function. The traditional idea of parallel processing within the basal ganglia is also challenged by recent findings. It is now clear that axons of GP neurons form large, perisomatic baskets around target neurons in all major basal ganglia nuclei, thereby exerting a profound influence on the output of the entire basal ganglia. GP neurons are autonomously active both in vivo and in vitro. It is believed that temporal information carried along the corticostriatopallidal pathway is critical for proper motor execution. The importance of appropriately controlled discharge of GP neurons is highlighted by psychomotor disorders such as Parkinson's disease, in which alterations in the pattern and synchrony of discharge in GP neurons are thought to contribute to motor symptoms. Several lines of evidence suggest that the aberrant activity of GP neurons following dopamine depletion is caused by alteration in the synaptic input from both striatum and subthalamic nucleus. In normal subjects, the capability of striatal input in translating cortical input into precisely timed responses in GP neurons is mediated by (1) the expression of postsynaptic GABA(A) receptor composed of subunits with fast kinetic properties; (2) an effective GABA reuptake system in terminating the action of synaptically released GABA, and (3) the existence of dendritic HCN channels that actively abbreviate the time course of the inhibitory postsynaptic potentials and reset rhythmic discharge. Despite the rapid pace in uncovering the elements that shape the activity along the striatopallidosubthalamic pathway, the origin of rhythmic, synchronized bursting of GP neurons seen in parkinsonism has not been fully established experimentally. Further elucidation of the factors that control the information transfer in the striatopallidal synapses is thus critical to our understanding of basal ganglia function and establishing treatment for Parkinson's disease and other basal ganglia disorders.     

Contributions of functional imaging to understanding parkinsonian symptoms

Brain imaging experiments identify plausible circuits involved in the genesis of the cardinal symptoms of Parkinson's disease. Akinesia is linked to hypoactivation of the supplementary motor area secondary to insufficient thalamocortical facilitation. Overactivation in other areas such as the lateral premotor and parietal cortex probably represents a compensatory mechanism. Bradykinesia is associated with abnormal functioning within intrinsic basal ganglia circuitry for scaling movements to appropriate magnitude. Parkinson's disease tremor is localized to pontine- and mesencephalic-cerebellar-thalamic circuits, with abnormalities of both dopamine and serotonin neurotransmission. There is a need to understand the anatomic intersections where information is shared across these circuits.     

Factors regulating the activity of striatal neurons: New perspectives fromin situ hybridization histochemistry

1. The basal ganglia contain a variety of putative peptide neurotransmitters. In situ hybridization allows changes in the levels of the mRNAs encoding these neuropeptides to be assessed at the cellular level of resolution. 2. Alterations in the activity of pathways within the basal ganglia of the rat produce distinct effects on the different neuropeptide mRNAs. 3. The evidence, where available, suggests that mRNA levels provide an index of peptide turnover. 4. This approach has consequently revealed much new information on the regulation of neuronal activity in the basal ganglia.     

GluR1 glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation

Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.     

Role of manganese in neurodegenerative diseases

Manganese (Mn) is an essential ubiquitous trace element that is required for normal growth, development and cellular homeostasis. Exposure to high Mn levels causes a clinical disease characterized by extrapyramidal symptom resembling idiopathic Parkinson's disease (IPD). The present review focuses on the role of various transporters in maintaining brain Mn homeostasis along with recent methodological advances in real-time measurements of intracellular Mn levels. We also provide an overview on the role for Mn in IPD, discussing the similarities (and differences) between manganism and IPD, and the relationship between α-synuclein and Mn-related protein aggregation, as well as mitochondrial dysfunction, Mn and PD. Additional sections of the review discuss the link between Mn and Huntington's disease (HD), with emphasis on huntingtin function and the potential role for altered Mn homeostasis and toxicity in HD. We conclude with a brief survey on the potential role of Mn in the etiologies of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and prion disease. Where possible, we discuss the mechanistic commonalities inherent to Mn-induced neurotoxicity and neurodegenerative disorders.     

Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson's disease. For this reason, we investigated the role of group-III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3 S )-3-[(3-amino-3-carboxypropyl(hydroxy)phosphinyl)-hydroxymethyl]-5-nitrothiophene (LSP1-3081) and l -2-amino-4-phosphonobutanoate (L-AP4). Here, we show that both drugs dose-dependently reduced glutamate- and GABA-mediated post-synaptic potentials, and increased the paired-pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post-synaptic currents. Their inhibitory effect was abolished by ( RS )-α-cyclopropyl-4-phosphonophenylglycine and was lost in slices from mGlu4 knock-out mice. Furthermore, ( S )-3,4-dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1-3081 or L-AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.     

苍白球γ-氨基丁酸能神经传递及其与神经系统疾病的关系

苍白球是基底神经节间接环路的重要核团,在机体运动功能调节中发挥重要作用。近年来,苍白球在基底神经节正常及异常功能调节中的重要性已日渐受到重视。然而,目前对苍白球内各种神经递质系统的功能活动了解较少。GABA是苍白球主要的神经递质。采用电生理记录、免疫组织化学及行为测试等实验方法,人们对大鼠苍白球GABA能神经传递系统的受体分布及功能活动有了新的认识。形态学研究揭示,苍白球存在GABAA受体及其苯二氮卓结合位点和GABAB受体。在亚细胞水平,GABAA受体主要位于对称性突触(GABA能突触)的突触后膜,而GABAB受体则位于对称性突触和非对称性突触(兴奋性突触)的突触前膜及突触后膜。功能学研究进一步揭示,激活苍白球突触前膜GABAB自身和异源性受体可分别减少GABA和谷氨酸释放;激活突触后膜GABAB受体,可引起苍白球神经元超极化。除GABAB受体外,激活苍白球GABAA受体苯二氮卓结合位点及阻断GABA重摄取可延长GABA电流持续时间,从而改变苍白球神经元兴奋性。与离体实验结果相一致,激活苍向球GABAB受体和苯二氮卓结合位点及阻断GABA重摄取可引起整体动物旋转行为。苍白球GABA神经递质系统与帕金森病病因学及癫痫发病有关。已证实,苍白球神经元放电频率的降低及簇状放电的产生与帕金森病运动减少及静止性震颤等症状直接相关。此外,电牛理及行为学实验发现,新型抗癫痫药物替加平可调节苍白球神经元功能活动．这为进一步了解苍白球与癫痫发病的关系提供了新的理论及实验依据。     

Comprehensive in vivo mapping of the human basal ganglia and thalamic connectome in individuals using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects.     

Effects of GABA and GABA receptor inhibition on differentiation of mesencephalic precursors into dopaminergic neurons in vitro

Neurotransmitters have been shown to control CNS neurogenesis, and GABA-mediated signaling is thought to be involved in the regulation of nearly all key developmental stages. Generation of dopaminergic (DA) neurons from stem/precursor cells for cell therapy in Parkinson's disease has become a major focus of research. However, the possible effects of GABA on generation of DA neurons from proliferating neurospheres of mesencephalic precursors have not been studied. In the present study, GABA(A), and GABA(B) receptors were found to be located in DA cells. Treatment of cultures with GABA did not cause significant changes in generation of DA cells from precursors. However, treatment with the GABA(A) receptor antagonist bicuculline (10(-5) M) led to a significant increase in the number DA cells, and treatment with the GABA(B) receptor antagonist CGP 55845 (10(-5) M) to a significant decrease. Simultaneous treatment with bicuculline and CGP 55845 did not induce significant changes. Apoptotic cell death studies and bromodeoxyuridine immunohistochemistry indicated that the aforementioned differences in generation of DA neurons are not due to changes in survival or proliferation of DA cells, but rather to increased or decreased differentiation of mesencephalic precursors towards the DA phenotype. The results suggest that these effects are exerted via GABA receptors located on DA precursors, and are not an indirect consequence of effects on the serotonergic or glial cell population. Administration of GABA(A) receptor antagonists in the differentiation medium may help to obtain higher rates of DA neurons for potential use in cell therapy for Parkinson's disease.     

Neuronal electrical high frequency stimulation enhances GABA outflow from human neocortical slices

Electrical high frequency stimulation of the globus pallidus internus or the subthalamic nucleus has beneficial motor effects in advanced Parkinson's disease. The mechanisms underlying these clinical results remain, however, unclear. From previous studies it is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of electrical high frequency stimulation. In these experiments, human neocortical slices were stimulated electrically (130 Hz) in vitro, and GABA outflow was measured after o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. Our results could demonstrate that high frequency stimulation (HFS) significantly increased basal GABA outflow in the presence of submaximal concentrations of the voltage-gated sodium channel opener veratridine. This effect could be abolished by the GABA antagonists bicuculline or picrotoxin. These results suggest that HFS has an activating effect on GABAergic neuronal terminals in human neocortical slices, depending on sodium and chloride influx. Since GABA plays a role in CNS disorders of basal ganglia, anxiety and epilepsy, its neocortical modulation by HFS may be (patho)physiologically relevant.     

Basal ganglia oscillations and pathophysiology of movement disorders

Low frequency rest tremor is one of the cardinal signs of Parkinson's disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinson's disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinson's disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.     

Manganese accumulation in the CNS and associated pathologies

Manganese (Mn) is an essential metal for life. It is a key constituent of clue enzymes in the central nervous system, contributing to antioxidant defenses, energetic metabolism, ammonia detoxification, among other important functions. Until now, Mn transport mechanisms are partially understood; however, it is known that it shares some mechanisms of transport with iron. CNS is susceptible to Mn toxicity because it possesses mechanisms that allow Mn entry and favor its accumulation. Cases of occupational Mn exposure have been extensively reported in the literature; however, there are other ways of exposure, such as long-term parental nutrition and liver failure. Manganism and hepatic encephalopathy are the most common pathologies associated with the effects of Mn exposure. Both pathologies are associated with motor and psychiatric disturbances, related in turn to mechanisms of damage such as oxidative stress and neurotransmitters alterations, the dopaminergic system being one of the most affected. Although manganism and Parkinson??s disease share some characteristics, they differ in many aspects that are discussed here. The mechanisms for Mn transport and its participation in manganism and hepatic encephalopathy are also considered in this review. It is necessary to find an effective therapeutic strategy to decrease Mn levels in exposed individuals and to treat Mn long term effects. In the case of patients with chronic liver failure it would be worthwhile to test a low-Mn diet in order to ameliorate symptoms of hepatic encephalopathy possibly related to Mn accumulation.     

Gene therapy for Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.     

The endogenous opioid system in neurological disorders of the basal ganglia

The endogenous opioid peptides have for some time been implicated in the regulation of motor behavior in animals. Recently, however, there is increased evidence to suggest a role for these peptides in the control of human motor functions as well as in the pathophysiology of abnormal movement disorders. Degeneration of opioid peptide-containing neurons in the basal ganglia has been demonstrated in Parkinson's disease and Huntington's chorea, but the clinical significance of these findings is largely unknown. On the other hand, there is evidence that excessive opioid activity may be important in the pathophysiology of some movement disorders such as tardive dyskinesia, progressive supra-nuclear palsy, and a subgroup of Tourette's patients. These findings indicate that diseases of the basal ganglia are possibly associated with alterations in opioid peptide activity, and that these alterations may be useful in designing experimental therapeutic strategies in these conditions.     

Stepping out of the box: information processing in the neural networks of the basal ganglia

The Albin-DeLong 'box and arrow' model has long been the accepted standard model for the basal ganglia network. However, advances in physiological and anatomical research have enabled a more detailed neural network approach. Recent computational models hold that the basal ganglia use reinforcement signals and local competitive learning rules to reduce the dimensionality of sparse cortical information. These models predict a steady-state situation with diminished efficacy of lateral inhibition and low synchronization. In this framework, Parkinson's disease can be characterized as a persistent state of negative reinforcement, inefficient dimensionality reduction, and abnormally synchronized basal ganglia activity.     

Manganese neurotoxicity: a model for free radical mediated neurodegeneration?

In man, manganese neurointoxication is characterised in the early phase by behavior reminiscent of that observed in schizophrenia. During chronic manganese intoxication the neuropsychiatric symptoms manifested earlier disappear and are followed by a permanent neurological phase typified by extrapyramidal symptoms similar to those of Parkinson's disease. Study of manganese intoxication in animals may provide important clues towards elucidation of the biochemical defect underlying neuropsychiatric as well as extrapyramidal disease. Investigations in our laboratory suggest that neurotoxicity of manganese is an exaggeration of function in normal neuronal homeostasis. Manganese neurointoxication in neonatal rats resulted in significant depression of lipid peroxidation in several rat brain regions examined. In the striatum, lipid peroxidative activity was abolished, an effect which may be related to alteration in neurotransmitters often observed in the striatum of manganese treated rats. The chronic, extrapyramidal stage of manganism, may ensue when excess Mn2+ is oxidised to higher valency forms where it can potentiate the autoxidation of catecholamines, like dopamine, resulting in concomitant formation of free radicals and cytotoxic quinones. This latter effect may arise preferentially in the substantia nigra, where neuromelanin is formed nonenzymatically by autoxidation of dopamine.     

Differential regulation of glutamate, aspartate and gamma-amino-butyrate release by N-methyl-D-aspartate receptors in rat striatum after partial and extensive lesions to the nigro-striatal dopamine pathway.

The in vivo microdialysis methodology was used to assess the effect of N-methyl-D-aspartate (NMDA) receptor ligands on glutamate (GLU), aspartate (ASP) and gamma-aminobutyrate (GABA) extracellular levels in the striatum of anaesthetized rats, after damage to the dopamine (DA) nigrostriatal pathway by injections of different doses of 6-hydroxydopamine (6-OH-DA) seven days earlier. The 6-OH-DA treated rats were divided into two groups, corresponding to animals with 20-80% (partial) and 85-99% (extensive) striatal DA tissue depletion, respectively. In rats with partial DA depletion, the striatal extracellular ASP levels significantly increased after intrastriatal dialysis perfusion with MK-801 (100 microM), an antagonist of NMDA receptors. In addition, a change in the pattern of local NMDA (500 microM)- induced efflux of ASP was observed in the striatum of these rats. However, in these partially DA-depleted striata no changes were found in basal extracellular levels of GLU, ASP and GABA or in NMDA- and MK-801-mediated effluxes of GLU and GABA relative to striata from sham rats. In contrast, rats with extensive striatal DA depletion exhibited a significant increase in ASP and GABA extracellular striatal levels, after intrastriatal dialysis perfusion with NMDA. In addition, the MK-801-mediated stimulation of extracellular ASP levels was accentuated along with the appearance of a MK-801 mediated increase in extracellular striatal GLU. Finally, basal extracellular levels of ASP, but not of GLU and GABA, were found to increase in extensive DA-depleted striata when compared to sham and partially DA-depleted striata. Thus, a differential regulation of basal and NMDA receptor-mediated release of transmitter amino acids occur seven days after partial and extensive DA-depleted striatum by 6-OH-DA-induced lesions of the nigrostriatal DA pathway. These findings may have implications as regards the participation of NMDA receptors in the compensatory mechanisms associated with the progress of Parkinson's disease, as well as in the treatment of this neurological disorder.