Cellular Mechanisms of Brain Energy Metabolism. Relevance to Functional Brain Imaging and to Neurodegenerative Disordersa (original) (raw)
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Proceedings of the National Academy of Sciences, 1994
Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na+-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis-i.e., glucose utilization and lactate production-in astrocytes. This metabolic action is mediated by activation of a Na+-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K+-ATPase, which is activated by an increase in the intraceliular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
The Journal of neuroscience, 2003
Glutamate stimulates glycolysis in astrocytes, a phenomenon that couples astrocytic metabolism with neuronal activity. However, it is not known whether glutamate also affects glucose transporter-1 (GLUT1), the transporter responsible for glucose entry into astrocytes. To address this question, two different real-time single-cell hexose uptake assays were applied to cultured hippocampal astrocytes using confocal epifluorescence microscopy. Glutamate caused a twofold to threefold increase in the zero-trans uptake rates of the fluorescent hexoses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) and 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4yl)amino]-6-deoxyglucose (6-NBDG). Galactose uptake, determined by the calcein volumetric assay, was stimulated to a similar extent, confirming the fluorescent hexose data, and also demonstrating that glutamate stimulation is a V max effect. Remarkably, glucose transport stimulation developed fully inside 10 sec, which is 100 times faster than acute stimulations of glucose transport in other cell types. Glutamate did not significantly affect the rate of 6-NBDG uptake by GLUT1-expressing epithelial Clone 9 cells, suggesting that an astrocyte-specific factor is required for transport stimulation. We conclude that glucose transport stimulation occurs early during astrocytic activation by glutamate, which provides a novel regulatory node to current models of brain energy metabolism. This mechanism should also be considered for the interpretation of functional imaging data based on hexoses.
Proceedings of the National Academy of Sciences, 2014
Significance A near one-to-one relationship had previously been observed between increments in the fluxes of the glutamate−glutamine neurotransmitter cycle and neuronal glucose oxidation in the tricarboxylic acid (TCA) cycle. This flux relationship was consistent with a hypothesized mechanism involving glycolytic ATP in astrocytes and astrocyte-to-neuron lactate shuttling. Here, 2-fluoro-2-deoxy- d -glucose was used to evaluate the glucose flux through glycolysis and the TCA cycle in nerve terminals isolated from the brains of rats under baseline and high-activity conditions. In a direct contradiction of this hypothesis, the results show that nerve terminals metabolize significant amounts of glucose.
Journal of neuroscience research, 2015
Cultured astrocytes treated with siRNA to knock down glutamate dehydrogenase (GDH) were used to investigate whether this enzyme is important for the utilization of glutamate as an energy substrate. By incubation of these cells in media containing different concentrations of glutamate (range 100-500 µM) in the presence or in the absence of glucose, the metabolism of these substrates was studied by using tritiated glutamate or 2-deoxyglucose as tracers. In addition, the cellular contents of glutamate and ATP were determined. The astrocytes were able to maintain physiological levels of ATP regardless of the expression level of GDH and the incubation condition, indicating a high degree of flexibility with regard to regulatory mechanisms involved in maintaining an adequate energy level in the cells. Glutamate uptake was found to be increased in these cells when exposed to increasing levels of extracellular glutamate independently of the GDH expression level. Moreover, increased intracell...
Cerebral Cortex, 1996
Survey of Brain Energy Metabolism at the Organ and Regional Levels Organ Level Fundamental observations on brain energy metabolism at the organ level culminated over 40 years ago, in particular through the pioneering work of Schmidt and Kety (1948). By determining arteriovenous (A-V) differences of a number of metabolic substrates the view emerged that, except under certain nonphysiological conditions, glucose is the obligatory energy substrate for the brain (Edvinsson et al., 1993). Glucose utilization by the brain is 31 u.mol/100 gm/min, while oxygen consumption is 160 (i.mol/100 gm/min; since CO 2 production is almost identical, the respiratory quotient (RQ) • of the brain is nearly 1, indicating that carbohydrates are the substrates for oxidative metabolism (Sokoloff, I960). With a global blood flow of 57 ml/100 gm/min, the brain extracts approximately 50% of oxygen and 10% of glucose from the arterial blood. Given a theoretical stoichiometry of 6 n.mol of oxygen consumed for each |i.mol of glucose, the expected brain glucose utilization should in theory be 26.6 fi.mol/100 gm/min rather than the measured 31 |imol/100 gm/min; thus, an excess of 4.4 |jt,mol/100 gm/min of glucose follows other metabolic fates. These include the production of lactate and pyruvate which do not necessarily enter the tricarboxylic acid cycle, but rather, can be released into the circulation. Glucose can also be incorporated into lipids, proteins, and glycogen, and it is the precursor of certain neurotransmitters such as GABA, glutamate, and acetylcholine (Sokoloff, 1989; Edvinsson et al., 1993). It should also be noted that a limited proportion of oxygen is actually utilized for purposes other that direct energy generation. Neural cells contain oxydases and hydroxylases, which are key regulatory enzymes in the metabolic pathways of a number of neuroactive molecules. Examples of such oxygen-requiring enzymes are cyclooxygenases and lipoxygenases involved in the synthesis of eicosanoids from arachidonic acid, tyrosine and tryptophan hydroxylases, dopamine-B-hydroxylase, and monoamine oxidase, •which are all enzymes that regulate the metabolism of monoamine neurotransmitters (Keevil and Mason, 1978). The recendy discovered NO synthase pathway also consumes oxygen (Klatt et al., 1993). Certain metabolic intermediates, under particular conditions, can substitute for glucose as alternative substrates for brain energy metabolism (Sokoloff, 1989)-Thus starvation, diabetes, or breast-feeding in neonates all lead to increased plasma levels of the ketone bodies acetoacetate and D-3-hydroxybutyrate, which can be used by the brain as metabolic substrates (Sokoloff, 1989). Mannose, which is not normally present in die blood and cannot therefore be considered a physiological substrate, can sustain normal brain function in the absence of glucose. Lactate and pyruvate can sustain synaptic activity in vitro (Mcllwain and Bachelard, 1985; Schurr et al., 1988). Because of their limited permeability across the blood-brain barrier, they cannot adequately substitute for plasma glucose to maintain brain function (Pardridge and Old
Astrocytes Couple Synaptic Activity to Glucose Utilization in the Brain
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 1999
Astrocytes have functional characteristics that make them particularly well suited to couple glutamate uptake from the synaptic cleft to Na(+)-K(+)-ATPase activation and glucose utilization. The changes in glucose metabolism associated with these processes may provide signals detected by positron emission tomography.
Regional glucose metabolism and glutamatergic neurotransmission in rat brain in vivo
2004
Multivolume 1 H-[ 13 C] NMR spectroscopy in combination with i.v. [1,6-13 C2]glucose infusion was used to detect regional glucose metabolism and glutamatergic neurotransmission in the halothane-anesthetized rat brain at 7 T. The regional information was decomposed into pure cerebral gray matter, white matter, and subcortical structures by means of tissue segmentation based on quantitative T1 relaxation mapping. The 13 C turnover curves of [4-13 C]glutamate, [4-13 C]glutamine, and [3-13 C]glutamate ؉ glutamine were fitted with a two-compartment neuronal-astroglial metabolic model. The neuronal tricarboxylic acid cycle fluxes in cerebral gray matter, white matter, and subcortex were 0.79 ؎ 0.15, 0.20 ؎ 0.11, and 0.42 ؎ 0.09 mol͞min per g, respectively. The glutamate-glutamine neurotransmitter cycle fluxes in cerebral gray matter, white matter, and subcortex were 0.31 ؎ 0.07, 0.02 ؎ 0.04, and 0.18 ؎ 0.12 mol͞min per g, respectively. The exchange rate between the mitochondrial and cytosolic metabolite pools was fast relative to the neuronal tricarboxylic acid cycle flux for all cerebral tissue types.
Activity-dependent regulation of energy metabolism by astrocytes: An update
Glia, 2007
Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and lactate consumption by neurons provides a heuristically valid framework for experimental studies. In this context, it is necessary to provide a survey of recent developments and data pertaining to this model. Thus, here, we review very recent experimental evidence as well as theoretical arguments strongly supporting the original model and in some cases extending it. Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, lactate as a preferential oxidative substrate for neurons, and the notion of net lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron lactate shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.
Glutamate Increases Glycogen Content and Reduces Glucose Utilization in Primary Astrocyte Culture
Journal of Neurochemistry, 1990
The glycogen content of primary cultured astrocytes was approximately doubled by incubation with 1 mM~-glutamate or L-aspartate. Other amino acids and excitatory neurotransmitters were without effect. The increase in glycogen level was not blocked by the glutamate receptor antagonist kynurenic acid but was completely blocked by the glutamate uptake inhibitor threo-3-hydroxy-~,~-aspartate and by removal of Na+ from the medium. Incubation with radiolabeled glucose and glutamate revealed that the increased glycogen content was derived almost entirely from glucose. Glutamate at 1 mM was also found to cause a 53 f 12% decrease in glucose utilization and a 112 k 69% increase in glucosed-phosphate levels. These results suggest that the glycogen content of astrocytes is linked to the rate of glucose utilization and that glucose utilization can, in turn, be affected by the availability of alternative metabolic substrates. These relationships suggest a mechanism by which brain glycogen accumulation occurs during decreased neuronal activity. Key Words: Aspartate-Glia-2-Deoxyglucose-Excitatory amino acid-Glucose-6-phosphate-Methionine sulfoximine. Swanson R. A. et al. Glutamate increases glycogen content and reduces glucose utilization in primary astrocyte culture.