The activities in different neural cell types of certain enzymes associated with the metabolic compartmentation glutamate

Patel, Ambrish J.; Hunt, Anthony; Gordon, Roger; Balázs, R.

doi:10.1016/0165-3806(82)90091-8

Cited by 165 publications

(54 citation statements)

References 41 publications

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“…Most of Glu is found in neurons [28,29], with extracellular concentration of Glu normally remaining at relatively low levels (0.1-1 mM), because of its excitotoxicity. In glial cells, the Glu concentration is even lower [38] and thus, contributes virtually no signal to Glu in 1 H MRS.…”

Section: Discussionmentioning

confidence: 99%

“…Several 1 H MRS studies demonstrated that compared to younger populations, older subjects have reduced cerebral N-acetyl aspartate (NAA), a putative neuronal marker [27,42], suggesting neuronal loss or deficit in neuronal metabolism [4,6,35]. Since Glu is also located primarily in neurons [28,29] and its concentration in the brain most likely reflects neuronal integrity, it should also decrease with age, similar to the NAA. In contrast, glutamine (Gln), a precursor of Glu, is thought to be located predominantly in glial cells [21], and may be used to determine changes of glial cells during normal aging.…”

Section: Introductionmentioning

confidence: 99%

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Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

Kaiser

Schuff

Cashdollar

et al. 2005

Neurobiology of Aging

219

150

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Proton magnetic resonance spectroscopy was performed at 4 T to determine effects of age, region and gender on glutamate and glutamine in the normal human brain. Furthermore, glutamate and glutamine alterations with age were tested for correlations with other cerebral metabolites. Two 8 cm 3 volumes were selected in corona radiata and mesial motor cortex in normal subjects (N = 24) between 24 and 68 years old. Older subjects had lower glutamate concentration in the motor cortex compared to younger subjects (p < 0.001). In corona radiata, older subjects demonstrated a trend in higher glutamine compared to younger subjects (p = 0.05). Glutamate in the motor cortex was positively correlated with glutamine, N-acetyl aspartate and creatine. Reduced glutamate and Nacetyl aspartate in the motor cortex is consistent with neuronal loss/shrinkage with age. In conclusion, different patterns in association with normal aging in these brain regions were detected in this study.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

Kaiser

Schuff

Cashdollar

et al. 2005

Neurobiology of Aging

219

150

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“…Most of the metabolic evidence suggests that uptake by glia is the most important process. Most of the Glu is in neurons (51), as is most of the glutaminase activity (52), whereas astrocytes contain most of the glutamine (Gln) (51), all of the glutamine synthetase (42), and pyruvate carboxylase (63); they predominantly take up and metabolize acetate (74). Early studies showed that cerebral Glu metabolism is compartmentalized, involving two major metabolic pools of Glu (7,16,71).…”

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confidence: 99%

A mathematical model of compartmentalized neurotransmitter metabolism in the human brain

Gruetter¹,

Seaquist²,

Uğurbil

2001

American Journal of Physiology-Endocrinology and Metabolism

301

498

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Gruetter, Rolf, Elizabeth R. Seaquist, and Kâ mil Ugurbil. A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol Endocrinol Metab 281: E100-E112, 2001.-After administration of enriched [1-13 C]glucose, the rate of 13 C label incorporation into glutamate C4, C3, and C2, glutamine C4, C3, and C2, and aspartate C2 and C3 was simultaneously measured in six normal subjects by 13 C NMR at 4 Tesla in 45-ml volumes encompassing the visual cortex. The resulting eight time courses were simultaneously fitted to a mathematical model. The rate of (neuronal) tricarboxylic acid cycle flux (V PDH ), 0.57 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , was comparable to the exchange rate between (mitochondrial) 2-oxoglutarate and (cytosolic) glutamate (V x , 0.57 Ϯ 0.19 mol ⅐ g Ϫ1 ⅐ min Ϫ1 ), which may reflect to a large extent malate-aspartate shuttle activity. At rest, oxidative glucose consumption [CMR Glc(ox) ] was 0.41 Ϯ 0.03 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , and (glial) pyruvate carboxylation (V PC ) was 0.09 Ϯ 0.02 mol ⅐ g Ϫ1 ⅐ min Ϫ1. The flux through glutamine synthetase (V syn ) was 0.26 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 . A fraction of V syn was attributed to be from (neuronal) glutamate, and the corresponding rate of apparent glutamatergic neurotransmission (V NT ) was 0.17 Ϯ 0.05The ratio [V NT /CMR Glc(ox) ] was 0.41 Ϯ 0.14 and thus clearly different from a 1:1 stoichiometry, consistent with a significant fraction (ϳ90%) of ATP generated in astrocytes being oxidative. The study underlines the importance of assumptions made in modeling 13 C labeling data in brain.nuclear magnetic resonance; glutamate; neurotransmission; in vivo spectroscopy IN THE TRADITIONAL CONTEXT of neuroscience, the brain's tasks are mainly accomplished by the neurons, with the surrounding glial cells performing simple, passive tasks of maintaining the milieu required for optimal neurotransmission. However, the glial cells are more than just passive components in neuronal function, in that they are intimately involved in the process of neurotransmission through glial uptake of glutamate (Glu) from the synaptic cleft (64,77,78). Glu is the major excitatory neurotransmitter (62); it is present in the mammalian brain in high concentrations and is dynamically stored in presynaptic vesicles (73). Despite the high intracellular concentration of Glu, the extracellular concentration must be maintained very low (ϳ0.004 mM) to avoid excitotoxicity. Presynaptic release of Glu into the synaptic cleft therefore requires efficient uptake mechanisms, which are achieved by Glu transporters (2). Most of the metabolic evidence suggests that uptake by glia is the most important process. Most of the Glu is in neurons (51), as is most of the glutaminase activity (52), whereas astrocytes contain most of the glutamine (Gln) (51), all of the glutamine synthetase (42), and pyruvate carboxylase (63); they predominantly take up and metabolize acetate (74). Early studies showed that cerebral Glu metabolism is compartmentalized, involving two major metabolic po...

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“…On the other hand, radioactive glutamine is accumulated into cultured granule cells (32,29,38), and the glutamate synthesizing enzyme, glutaminase, was shown to have higher activity in cultured granule cells than in cultured astrocytes (39). For these reasons and also because the depolarization-induced release of endogenous (but not of exogenous) radioactive glutamate or D-aspartate was shown to be Ca2" dependent in cerebellar synaptosomal preparations (5,9), in the present investigation we analyzed the release ofendogenous glutamate and that ofradioactive glutamate synthesized by the cells from the immediate precursor glutamine (40,41).t…”

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confidence: 99%

Selective release of glutamate from cerebellar granule cells differentiating in culture

Gallo

Ciotti

Coletti

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

428

278

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The aim of the present study was to assess whether endogenous and newly synthesized glutamate can be released from differentiating cultured cerebellar granule cells in a way compatible with a neurotransmitter role. Granule cells from 8-day-old rat cerebella were grown in basal Eagle's medium with 10% fetal calfserum for 2-12 days in vtitro (DIV), then washed with Krebs-Ringer medium, and labeled for 45 min with tracer amounts of radioactive glutamine. Subsequently, the release of endogenous glutamate and ofnewly formed radioactive glutamate was measured in basal conditions and upon depolarization with elevated K+ concentration or veratridine. At 2 DIV, the release of endogenous and newly synthesized glutamate evoked by high K+ concentration was small and Ca 2 independent, but it progressively and steadily increased (up to 8-to 10-fold) and became Ca2" dependent (up to 80-85%) at later stages (4, 8, and 12 DIV).Veratridine was almost ineffective with cells at 2 DIV but greatly increased glutamate release (endogenous and neosynthesized) at 8 DIV, and its action was totally antagonized by tetrodotoxin. The level and synthesis of glutamate remained fairly constant in cells from 2 to 12 DIV. y-Aminobutyric acid synthesis from radioactive glutamine was about 3% of that ofglutamate, and y-aminobutyric acid release (endogenous and neosynthesized) was not measurable. Aspartate synthesis was about 10% of that of glutamate, and the high K+ concentration-evoked release of this amino acid was modest and scarcely affected by Ca2". Neither high K+ concentration nor veratridine was able to induce glutamate release from confluent cerebellar astrocyte cultures at 14 DIV, although the level and synthesis of the amino acid were comparable to those in granule cells. In conclusion, the data show that a stimulus-coupled release of endogenous and neosynthesized glutamate is progressively expressed by cerebellar granule cells differentiating in culture, and this strongly supports the concept that glutamate is the neurotransmitter of these cells.It is known that the excitatory information reaching the cerebellum through the mossy fibers is conveyed to the inhibitory neurons of the cerebellar cortex (mainly to the Purkinje cells) by excitatory interneurones-the granule cells (1), which represent the most abundant neuronal population of the cerebellar cortex. Although glutamic acid has been proposed as the excitatory transmitter of granule cells (2-7), largely on the basis of indirect neurochemical evidence, definitive proof substantiating this hypothesis is still lacking, and some data ofthe literature even appear to be in contrast with it. For example, the high affinity uptake and the concentration of glutamate were not found to be significantly decreased in cerebella severely depleted of granule cells (refs. 5 and 8; however, see refs. 2-7), as one would expect if a substantial glutamate pool were associated with these cells. Moreover, autoradiographic studies on cerebellar slices preincubated in the presence of low concentrati...

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The activities in different neural cell types of certain enzymes associated with the metabolic compartmentation glutamate

Cited by 165 publications

References 41 publications

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T

A mathematical model of compartmentalized neurotransmitter metabolism in the human brain

Selective release of glutamate from cerebellar granule cells differentiating in culture

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