Anne B. Young

The functional anatomy of basal ganglia disorders

Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinsons disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.

Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.

Huntingtons disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15–20 years and, at present, there is no effective treatment. The mutation in patients with Huntingtons disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M r 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntingtons disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntingtons disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntingtons disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntingtons disease.

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention. Getting to the Root of Parkinson’s Disease Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results in the loss of dopamine neurons in the substantia nigra of the brain. Degeneration of these movement-related neurons predictably causes rigidity, slowness of movement, and resting tremor, but patients also show cognitive changes. Although gene mutations have been identified in several families with PD, the cause of the more common sporadic form is not known. Certain environmental factors, such as exposure to the pesticide rotenone, combined with a genetic susceptibility, are thought to confer risk for developing PD. A key pathological feature seen in postmortem brain tissue from PD patients is Lewy bodies, neuronal inclusions containing clumps of the α-synuclein protein (which is mutated in familial PD), as well as damaged mitochondria. Taking a systems biology approach to pinpoint the root cause of PD, Zheng et al. now implicate altered activity of the master transcription factor PGC-1α and the genes it regulates in the early stages of PD pathogenesis. To detect new sets of genes that may be associated with PD, the investigators did a meta-analysis of 17 independent genome-wide gene expression microarray studies that had been performed on a total of 322 postmortem brain tissue samples and 88 blood samples. The samples came from presymptomatic and symptomatic PD patients, as well as from control individuals who did not show any neurological deficits at autopsy. Nine genome-wide expression studies were conducted either on dopaminergic neurons obtained by laser capture from substantia nigra (three studies) or on substantia nigra homogenates (six studies). The authors then used a powerful tool called Gene Set Enrichment Analysis to sift through 522 gene sets (a gene set is a group of genes involved in one biological pathway or process). At the end of this tour-de-force analysis, they identified 10 gene sets that were all associated with PD. The gene sets with the strongest association contained nuclear genes encoding subunits of the electron transport chain proteins found in mitochondria. These genes all showed decreased expression in substantia nigra dopaminergic neurons (obtained by laser capture) even in the earliest stages of PD. Furthermore, a second gene set associated with PD and also underexpressed in the earliest stages of PD encodes enzymes involved in glucose metabolism. These results are compelling because many studies have already implicated dysfunctional mitochondria and altered energy metabolism as well as defective glucose metabolism in PD. The authors realized that these gene sets had in common the master transcriptional regulator, PGC-1α, and surmised that disruption of PGC-1α expression might be a root cause of PD. They tested this hypothesis in cultured dopaminergic neurons from embryonic rat midbrain forced to express a mutant form of α-synuclein. Overexpression of PGC-1α in these neurons resulted in activation of electron transport genes and protection against neuronal damage induced by mutant α-synuclein. In other cultured neurons treated with rotenone, overexpression of PGC-1α also was protective, blocking pesticide-induced neuronal cell death. These exciting findings identify altered expression of PGC-1α and the genes it regulates as key players during early PD pathogenesis. This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs. Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Excitatory amino acids and Alzheimer's disease.

Excitatory amino acids (EAA) such as glutamate and aspartate are major transmitters of the cerebral cortex and hippocampus, and EAA mechanisms appear to play a role in learning and memory. Anatomical and biochemical evidence suggests that there is both pre- and postsynaptic disruption of EAA pathways in Alzheimers disease. Dysfunction of EAA pathways could play a role in the clinical manifestations of Alzheimers disease, such as memory loss and signs of cortical disconnection. Furthermore, EAA might be involved in the pathogenesis of Alzheimers disease, by virtue of their neurotoxic (excitotoxic) properties. Circumstantial evidence raises the possibility that the EAA system may partially determine the distribution of pathology in Alzheimers disease and may be important in producing the neurofibrillary tangles, RNA reductions and dendritic changes which characterize this devastating disorder. In this article, we will review the evidence suggesting a role for EAA in the clinical manifestations and pathogenesis of Alzheimers disease.

Excitatory amino acid binding sites in the basal ganglia of the rat: A quantitative autoradiographic study

Quantitative receptor autoradiography was used to determine the distribution of excitatory amino acid binding sites in the basal ganglia of rat brain. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, kainate, quisqualate-sensitive metabotropic and non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had their highest density in striatum, nucleus accumbens, and olfactory tubercle. Kainate binding was higher in the lateral striatum but there was no medial-lateral striatal gradient for other binding sites. N-Methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding sites were most dense in the nucleus accumbens and olfactory tubercle. There was no dorsal-ventral gradient within the striatal complex for the other binding sites. Other regions of the basal ganglia had lower densities of ligand binding. To compare binding site density within non-striatal regions, binding for each ligand was normalized to the striatal binding density. When compared to the striatal complex, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and metabotropic binding sites had higher relative density in the globus pallidus, ventral pallidum, and subthalamic nucleus than other binding sites. Metabotropic binding also had a high relative density in the substantia nigra. Non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had a high relative density in globus pallidus, ventral pallidum, and substantia nigra. N-Methyl-D-aspartate binding sites had a low relative density in pallidum, subthalamic nucleus, substantia nigra and ventral tegmental area. Our data indicate heterogeneous distribution of excitatory amino acid binding sites within rat basal ganglia and suggest that the character of excitatory amino acid-mediated neurotransmission within the basal ganglia is also heterogeneous.

Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches.

In last months article in this series, Lodge and Johnson discussed the contribution of noncompetitive excitatory amino acid antagonists to understanding of these receptors. In this third article, Anne Young and Graham Fagg describe how radioligand binding experiments have helped to fuel the recent burst of progress in understanding excitatory amino acid receptors in the brain. New and selective radioligands have facilitated mapping the distributions of the major excitatory receptor subtypes in normal and diseased brain, examining allosteric interactions within the NMDA receptor, searching for novel therapeutic agents and determining drug mechanisms, and making first steps along the path to defining receptor structure at the molecular level.

Glutamic acid: Selective depletion by viral induced granule cell loss in hamster cerebellum

Abstract Cerebellar hypoplasia in the hamster induced by rat virus strain PRE 308 was used as a model system in which greater than 95% of the cerebellar granule cell population can be selectively depleted at an early stage of development. Electron microscopic examination of infected hamster cerebella indicated a significant reduction of parallel fiber synapses and granule cell dendrites in glomeruli. All other cell types occurred in approximately normal numbers and formed proper synaptic connections. To attempt to identify the transmitter of the cerebellar granule cell, we examined the uptakes of amino acids and amines into synaptosomes in the cerebella of hamsters with granuloprival cerebellar hypoplasia and their littermate controls. The high affinity uptakes of glutamic and aspartic acids were reduced by 70% in infected animals. No significant reductions occurred in the uptakes of a variety of other amino acids, putative neurotransmitters and their precursors. Endogenous glutamic acid was decreased by 43%, although endogenous protein concentration was not altered. Analysis of the free cerebellar amino acid content of infected animals revealed a selective decrease in glutamic acid and no decrease in other amino acids, in particular aspartic acid. Partial granule cell depletions were also produced and the extent of granule cell loss correlated with the decrease in endogenous glutamic acid and high affinity glutamic acid uptake. Granule cells are excitatory in function; the neurophysiologic action of glutamic acid is also excitatory. Our findings suggest that glutamic acid is the natural neurotransmitter of the cerebellar granule cell.

Distribution and kinetics of GABAB binding sites in rat central nervous system: A quantitative autoradiographic study

[3H]GABA quantitative autoradiography was used to examine the binding kinetics and regional distribution of GABAB receptors in rat brain. The regional distribution was compared to that of GABAA receptors. At 4 degrees C, [3H]GABA binding to GABAB receptors reached equilibrium within 45 min. The association and dissociation rate constants for GABAB binding to outer neocortical layers were 2.87 +/- 0.17 X 10(5) min-1 M-1 and 0.0966 +/- 0.0118 min-1, respectively, indicating a dissociation constant of 336 +/- 40 nM. Saturation binding studies in the same region yielded a dissociation constant for GABAB receptors of 341 +/- 41 nM while that of GABAA receptors was 92 +/- 10 nM. While the affinities of each type of GABA receptor were uniform across brain regions, the maximal number of binding sites for both types of GABA receptor varied across regions. The distributions of the two receptors in rat brain were different in the olfactory bulb, cerebellum, thalamus, neocortex, medial habenula and interpeduncular nucleus. Areas high in GABAB binding included the medial and lateral geniculates, the superior colliculus and certain amygdaloid nuclei. Binding to white matter tracts and ventricles was negligible. The distribution of GABAB receptors was in agreement with previously postulated sites of action of baclofen.

Glutamate dysfunction in Alzheimer's disease: an hypothesis

Abstract Glutamate is a major excitatory neurotransmitter that has been implicated in memory formation and learning. This acidic amino acid also has neurotoxic properties, and in animals produces lesions reminiscent of human neurodegenerative diseases. Here we present evidence that supports the hypothesis that glutamate dysfunction is involved in the pathophysiology of Alzheimers disease and can account for many of the neurochemical and behavioral deficits observed in this disease.

The functional anatomy of disorders of the basal ganglia

T HE SUCCESS of our article’ in ITM on basal gan. glia pathophysiology is a result of several factors. First, the article was published in TINS, a widely respected and widely read forum for the disseminatlon of important concepts In contemporary neuroscience research. Second, QUI article had a particu larly broad focus and was afmed at putting clinical phenomena in the perspective of new developments in basal ganglia anatamy and physiolagy. We attempted an overview of anatomy and function that would be comprehenstble and useful to clinicians, and a systematic analysis of salient ciinfcal phenomena that could be interpreted by basic nemoscientists. The frequent citation of this article suggests that we achieved our objectives. Third, the article was publlshed at a time when several tndependent streams of research on the basal gaugfla were converging to reveal some basic unifying conceph: the segregation of shfatal output pathways, the differential regulation by dopaminergic afferents of stdatal output pathways, and the fmportance of the subthalamus in regulating motor behavior. Some of the concepts discussed III the arttcle had already been discussed widely and accepted wfthin the basal ganglia communip. We had the opportunity and the pleasure of attempting to weave these ideas into a coherent whole. Our seed fell on fertile ground that had been prepared well by the efforts of numerous colleagues. Finally. the explicit linkages between basic anatomy and physiology and clinical phenomenology proved to be very attractive to many sdeutMs. These ltnkages were made possible by advances In the understanding of Parkinson’s disease based on studies of animal models, and advances in the understandfng of Huntington’s disease derived from analysis of post-mortem tissue. Writing this article and witnessing its favorable reception proved to be satisfying for several reasons, The mode1 elaborated tn the article was the descendant of previous models developed by two of us (ABY and JSPY. The early models led to animal experiments that refuted ptedicrions derived from the earlier models, and spurred the development of a more sophisticated modt?P. Similarly, these and other animal experiments led to analyses of human post-mortem tissue with a view to understanding the pathophysiology of basal ganglia dysfunction*. The success of this hypothesis-driven enterprise testiftes to the importance of modelderived predictions as a means of advancing scientific understauding. The apparent success of this model is also an affirmation of the basic method of clinical neurology _ the clinicopathologic correlation, The use of data from analysts of post-mortem human material and animal models of basal ganglia disease is an extension of the correlative methods used by neurologists since the 19tb century. It was excittng to contribute to a tradition that was initiated by the founders of clinical