Excitatory amino acids directly depolarize rat brain astrocytes in primary culture

Bowman, Charles L.; Kimelberg, Harold K.

doi:10.1038/311656a0

Cited by 355 publications

(159 citation statements)

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“…In keeping with this, it has repeatedly been shown that astrocytes express a selection of glutamate receptors including kainate and AMPA receptors both of which are sensitive to kainate. 10,28,29 This was supported by several studies carried out in cultured astrocytes demonstrating alterations in cellular ion homeostasis after exposure to kainate including complex changes in intracellular concentrations of Na þ and H þ (see ref. 30) and increases in the extracellular K þ concentration likely due to increased astrocytic K þ efflux.…”

Section: Discussionmentioning

confidence: 66%

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Walls

Eyjolfsson

Schousboe

et al. 2014

J Cereb Blood Flow Metab

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Despite the well-established use of kainate as a model for seizure activity and temporal lobe epilepsy, most studies have been performed at doses giving rise to general limbic seizures and have mainly focused on neuronal function. Little is known about the effect of lower doses of kainate on cerebral metabolism and particularly that associated with astrocytes. We investigated astrocytic and neuronal metabolism in the cerebral cortex of adult mice after treatment with saline (controls), a subconvulsive or a mildly convulsive dose of kainate. A combination of [1,2-13 C]acetate and [1-13 C]glucose was injected and subsequent nuclear magnetic resonance spectroscopy of cortical extracts was employed to distinctively map astrocytic and neuronal metabolism. The subconvulsive dose of kainate led to an instantaneous increase in the cortical lactate content, a subsequent reduction in the amount of [4,[5][6][7][8][9][10][11][12][13] C]glutamine and an increase in the calculated astrocytic TCA cycle activity. In contrast, the convulsive dose led to decrements in the cortical content and 13 C labeling of glutamate, glutamine, GABA, and aspartate. Evidence is provided that astrocytic metabolism is affected by a subconvulsive dose of kainate, whereas a higher dose is required to affect neuronal metabolism. The cerebral glycogen content was dose-dependently reduced by kainate supporting a role for glycogen during seizure activity.

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Section: Discussionmentioning

confidence: 66%

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Walls

Eyjolfsson

Schousboe

et al. 2014

J Cereb Blood Flow Metab

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“…Depolarization of the membrane above Ϫ75 mV should, therefore, lead to inward Na ϩ / HCO 3 Ϫ cotransport. K A depolarizes astrocytes by 5 mV/sec (Backus et al, 1989); the total depolarization can reach 20 -25 mV (Bowman and Kimelberg, 1984;Kettenmann and Schachner, 1985). The similar time courses of K A-induced alkalinization and depolarization (see Bowman and Kimelberg, 1984;Kettenmann and Schachner, 1985;Backus et al, 1989) strongly suggest that the alkalinization resulted from accelerated inward Na ϩ / HCO 3 Ϫ cotransport during K A application (see above).…”

Section: Origin Of K A-evoked [H ؉ ] I Changesmentioning

confidence: 63%

“…Likewise Glu-induced acidifications were resistant to CNQX (they actually increased), demonstrating that they too were not caused by ionotropic non-NMDA receptor activation. Glu transport is voltage dependent (Brew and Attwell, 1987), and if CNQX partially blocked the Glu-induced depolarization (Bowman and Kimelberg, 1984;Kettenmann and Schachner, 1985), Glu uptake and acidification would be increased. Reduction of Glu-induced depolarization also might have reduced a depolarization-dependent alkalinization process, thereby magnifying the acidification (see below).…”

Section: Origin Of Glu-and D-asp-evoked Acidificationsmentioning

confidence: 99%

Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

1996

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The excitatory transmitter glutamate (Glu), and its analogs kainate (KA), andd-aspartate (d-Asp) produce significant pH changes in glial cells. Transmitter-induced pH changes in glial cells, generating changes in extracellular pH, may represent a special form of neuronal–glial interaction. We investigated the mechanisms underlying these changes in intracellular H+concentration ([H+]i) in cultured rat hippocampal astrocytes and studied their correlation with increases in intracellular Na+concentration ([Na+]i), using fluorescence ratio imaging with 2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) or sodium-binding benzofuran isophthalate (SBFI). Glu, KA, ord-Asp evoked increases in [Na+]i; Glu ord-Asp produced parallel acidifications. KA, in contrast, evoked biphasic changes in [H+]i, alkaline followed by acid shifts, which were unaltered after Ca2+removal and persisted in 0 Cl−-saline, but were greatly reduced in CO2/HCO−3-free or Na+-free saline, or during 4,4′-diisothiocyanato-stilbene-2,2′-disulphonic acid (DIDS) application. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked KA-evoked changes in [H+]iand [Na+]i, indicating that they were receptor–ionophore mediated. In contrast, CNQX increased the [H+]ichange and decreased the [Na+]ichange induced by Glu.d-Asp, which is transported but does not act at Glu receptors, induced [H+]iand [Na+]ichanges that were virtually unaltered by CNQX. Our study indicates that [Na+]iincreases are not primarily responsible for Glu- or KA-induced acidifications in astrocytes. Instead, intracellular acidifications evoked by Glu ord-Asp are mainly caused by transmembrane movement of acid equivalents associated with Glu/Asp-uptake into astrocytes. KA-evoked biphasic [H+]ichanges, in contrast, are probably attributable to transmembrane ion movements mediated by inward, followed by outward, electrogenic Na+/HCO−3cotransport, reflecting KA-induced biphasic membrane potential changes.

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“…The astrocytic Na + /K + -ATPase responds predominantly to increases in intracellular Na + concentration ([Na + ] i ) for which it shows a K m of about 10 mM (Kimelberg et al 1993). Since in cultured astrocytes, the N[Na + ] i ranges between 10 and 20 mM (Kimelberg et al 1993), Na + /K + -ATPase is set to be readily activated when N[Na + ] i rises concomitantly with glutamate uptake (Bowman & Kimelberg 1984). Indeed, recent evidence obtained in our laboratory using 86 Rb uptake to directly monitor the activity of the pump, shows that glutamate activates the Na + /K + -ATPase , 1997.…”

Section: Synaptically Released Glutamate Triggers Glucose Use In Astrmentioning

confidence: 99%

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Magistretti¹,

Pellerin²

1999

Phil. Trans. R. Soc. Lond. B

670

458

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Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood £ow and energy metabolism. Positron emission tomography (PET) signals detect blood £ow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identi¢es the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic £uxes in puri¢ed preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identi¢ed the neurotransmitter glutamate and astrocytes, a speci¢c type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This e¡ect is mediated by speci¢c glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na + . This Na + -dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na + /K + -ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na + ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one`turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule....

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Excitatory amino acids directly depolarize rat brain astrocytes in primary culture

Cited by 355 publications

References 20 publications

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

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Excitatory amino acids directly depolarize rat brain astrocytes in primary culture

Cited by 355 publications

References 20 publications

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

Mechanisms of H+and Na+Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

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Product

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Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes