L-Glutamate binding sites of normal and atrophic human cerebellum

Tsiotos, P.; Plaitakis, Andreas; Mitsacos, Ada; Voukelatou, Georgia; Michalodimitrakis, Manolis; Kouvelas, Elias D.

doi:10.1016/0006-8993(89)90487-3

Cited by 21 publications

(14 citation statements)

References 37 publications

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“…Independent studies describe alterations to the glutamatergic system with age and suggest a role for Glu in cognitive functioning, but few animal and no human studies have demonstrated the functional significance of age-related alterations to the glutamatergic system. Autoradiography of postmortem rodent and human tissue demonstrates lower Glu receptor binding with older age in basal ganglia (Mitchell and Anderson 1998;Villares and Stavale 2001), cerebellum (Tsiotos et al 1989;Simonyi et al 2000), and hippocampus (Tamaru et al 1991;Court et al 1993). Chromatrographic assays detect age-related declines in total Glu concentration in homogenized rat cerebrum (Tyce and Wong 1980;Dawson et al 1989;Benuck et al 1995) but not autopsied putamen (Kornhuber et al 1993) or biopsied basal frontal, basal temporo-occipital, temporal, and parietal cortices (Knorle et al 1997) of human tissue.…”

Section: Introductionmentioning

confidence: 99%

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

et al. 2008

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Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glu's spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents-the striatum, cerebellum, and pons-and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

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Section: Introductionmentioning

confidence: 99%

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

et al. 2008

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“…On the other hand, patients who suffered from late-onset sporadic OPCA (cases 5 and 6) showed a marked decrease in L-glutamate binding in both molecular and granule cell layers. This decrease in binding probably reflects a degeneration of both Purkinje and granule cells and cannot be atrributed to the old age of the patients because, as our previous study has shown, the number of L-glutamate binding sites in human cerebellum is almost equal between ages 23 and 80 years (Tsiotos et al, 1989). Finally, the patient who suffered from a form of OPCA inherited in a dominant manner and who died at the age of 15 years also showed a marked decrease in L-glutamate binding in the molecular layer and in the granule cell layer.…”

Section: Inhibition Of L-[3h]glutamate Bindingmentioning

confidence: 88%

“…Because of the small amount of tissue which was available, especially from OPCA patients, the inhibition of binding of L-[3H]glutamate by the different agonists and antagonists was measured only at the concentration of 100 pM (concentration of maximal inhibition). Because of previous reports showing that quisqualate inhibits L-[3H]glutamate binding in a biphasic manner in both human and rat brain (Tsiotos et al, 1989;Cha et al, 1988;Greenamyre et al, 1984;Werling et al, 1983), this drug was used in the control tissues in two concentrations (2.5 and 100 pM). The same concentrations were also used in similar autoradiographic studies in rat, mouse, and human brain (Cha et al, 1988;Olson et al, 1987;Greenamyre et al, 1987).…”

Section: Inhibition Of L-[3h]glutamate Bindingmentioning

confidence: 99%

“…If the above neuroexcitotoxic hypothesis for OPCA is correct, one would expect to find in this disease a selective disappearance of postsynaptic elements that bear glutamate receptors. With these considerations in mind, we have recently examined L-glutamate binding in membranes of cerebellar postmortem material from four OPCA patients (Tsiotos et al, 1989). This study showed a 70% decrease in B, , , of L-glutamate binding in all OPCA patients examined with no change in K,.…”

Section: Introductionmentioning

confidence: 97%

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Quantitative autoradiographic study of L‐glutamate binding sites in normal and atrophic human cerebellum

Hatziefthimiou

Mitsacos

Mitsaki

et al. 1991

J of Neuroscience Research

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In the present work the distribution of L-glutamate binding sites in the different layers of human cerebellum of normal individuals and of seven patients who died with olivopontocerebellar atrophy (OPCA) was examined with the technique of quantitative autoradiography. Specific L-[3H]glutamate binding was higher in the molecular than in the granule cell layer of normal cerebellar tissue. A significant decrease of L-[3H]glutamate specific binding was observed in the molecular layer of all OPCA tissues. In the granule cell layer L-[3H]glutamate binding was decreased only in two patients who suffered from late-onset sporadic OPCA and in one patient who suffered from a form of OPCA inherited in a dominant manner. Quisqualate-sensitive binding sites were the most abundant binding sites in the molecular layer of normal cerebella, whereas N-methyl-D-aspartic acid (NMDA)-sensitive binding sites were the most abundant type in the granule cell layer. A significant decrease of quisqualate-sensitive and an increase in NMDA-sensitive binding sites were observed in the molecular layer of OPCA cerebellar tissues. No significant changes were observed in the granule cell layer of these tissues.

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“…10 Results revealed the L-glutamate binding was significantly decreased (to 30% of control) in all these patients without a change in the affinities and the pharmacologic properties of the binding sites. 42 Additional autoradiographic studies 43 showed significant decreases in quisqualate-sensitive L-glutamate binding in the molecular layer of the cerebellum. In some patients, particularly those associated with GDH abnormalities, L-glutamate binding was decreased in the granule layer as well.…”

Section: L-glutamate Receptors In Opcamentioning

confidence: 99%

Glutamate Dehydrogenase Deficiency in Cerebellar Degenerations: Clinical, Biochemical and Molecular Genetic Aspects

Plaitakis

Flessas

Natsiou

et al. 1993

Can. J. Neurol. Sci.

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Glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism, is significantly reduced in patients with heterogenous neurological disorders characterized by multiple system atrophy (MSA) and predominant involvement of the cerebellum and its connections. In human brain, GDH exists in multiple isoforms differing in their isoelectric point and molecular mass. These are differentially reduced in quantity and altered in catalytic activity in patients with clinically distinct forms of MSA, thus suggesting that these GDH isoproteins are under different genetic control. Dysregulation of glutamate metabolism occurs in patients with GDH deficiency and is thought to mediate the disease's neurodegeneration via neuroexcitotoxic mechanisms. This possibility is supported by additional data showing that glutamate binding sites are significantly decreased in cerebellar tissue obtained at autopsy from MSA patients. At the molecular biological level, several cDNAs specific for human GDH have been isolated recently and cloned. Northern blot analysis of various human tissues, including brain, has revealed the presence of multiple GDH-specific mRNAs. In addition, multiple GDH-specific genes are present in humans and these data are consistent with the possibility that the various GDH isoproteins are encoded by different genes. These advances have laid the groundwork for characterizing the human GDH genes and their products in health and disease. RESUME: Deficit en glutamate dehydrogenase dans les degenerescences cerebelleuses: aspects cliniques, biochimiques et de genetique moleculaire. La glutamate dehydrogenase (GDH), un enzyme important du metabolisme du glutamate, est diminuee de facon significative chez les patients souffrant de maladies neurologiques heterogenes caracterisees par une atrophie multi-systemique (AMS) et une atteinte principalement localisee au cervelet et a ses voies de communication. Dans le cerveau humain, la GDH existe sous de multiples isoformes, qui different par leur point isoelectrique et leur masse moleculaire, dont la quantite est diminuee differentiellement et dont l'activite catalytique est alteree, chez les patients qui ont des formes d'AMS cliniquement distinctes, suggerant que ces isoproteines sont sous un controle genetique different. Un dereglement du metabolisme du glutamate survient chez les patients qui ont un deficit en GDH et Ton pense qu'il est a l'origine de la neurodegenerescence presente dans cette maladie via des mecanismes neuro-excitotoxiques. Des donnees additionnelles supportent cette possibilite: les sites de liaison du glutamate sont diminues de facon significative dans le tissu cerebelleux provenant d'autopsies de patients atteints d'AMS. Au niveau de la biologie moleculaire, plusieurs ADN complementaires specifiques pour la GDH humaine ont ete isoles et clones recemment. L'analyse par Northern blot de differents tissus humains incluant le cerveau, a revele la presence de multiples ARN messagers specifiques de la GDH. De plus, plusieurs genes specifiques a la ...

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L-Glutamate binding sites of normal and atrophic human cerebellum

Cited by 21 publications

References 37 publications

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Quantitative autoradiographic study of L‐glutamate binding sites in normal and atrophic human cerebellum

Glutamate Dehydrogenase Deficiency in Cerebellar Degenerations: Clinical, Biochemical and Molecular Genetic Aspects

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