Glutamate Triggers Rapid Glucose Transport Stimulation in Astrocytes as Evidenced by Real-Time Confocal Microscopy

Loaiza, Anitsi; Porras, Omar; Barros, L. Felipe

doi:10.1523/jneurosci.23-19-07337.2003

Cited by 234 publications

(217 citation statements)

References 34 publications

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“…To this aim, electrical stimulations of astrocytes were performed under the same conditions as those described above in the presence of the fluorescent glucose analogue 2-NBD-glucose, which was used as a tracer to evaluate the spatial distribution of glucose uptake. This fluorescent glucose analogue has been shown to undergo rapid transport in astrocytes, which was enhanced by the presence of glutamate (29). Fig.…”

Section: Na Imentioning

confidence: 96%

Astrocytes generate Na ⁺ -mediated metabolic waves

Bernardinelli

Magistretti²,

Chatton³

2004

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

170

145

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Glutamate-evoked Na ؉ increase in astrocytes has been identified as a signal coupling synaptic activity to glucose consumption. Astrocytes participate in multicellular signaling by transmitting intercellular Ca 2؉ waves. Here we show that intercellular Na ؉ waves are also evoked by activation of single cultured cortical mouse astrocytes in parallel with Ca 2؉ waves; however, there are spatial and temporal differences. Indeed, maneuvers that inhibit Ca 2؉ waves also inhibit Na ؉ waves; however, inhibition of the Na ؉ ͞glutamate cotransporters or enzymatic degradation of extracellular glutamate selectively inhibit the Na ؉ wave. Thus, glutamate released by a Ca 2؉ wave-dependent mechanism is taken up by the Na ؉ ͞glutamate cotransporters, resulting in a regenerative propagation of cytosolic Na ؉ increases. The Na ؉ wave gives rise to a spatially correlated increase in glucose uptake, which is prevented by glutamate transporter inhibition. Therefore, astrocytes appear to function as a network for concerted neurometabolic coupling through the generation of intercellular Na ؉ and metabolic waves.

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Section: Na Imentioning

confidence: 96%

Astrocytes generate Na ⁺ -mediated metabolic waves

Bernardinelli

Magistretti²,

Chatton³

2004

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

170

145

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“…Glutamate inhibits NBDG transport into cultured neurons (Porras et al, 2004; Table 3) and stimulates glucose transport into cultured astrocytes (Loaiza et al, 2003; Table 1). These findings have been interpreted by Pierre et al (2009) as rerouting of glucose from neurons to astrocytes during glutamatergic neurotransmission, so neurons would depend on astrocyte-derived lactate as a fuel, in accordance with the astrocyte-neuron lactate shuttle hypothesis.…”

Section: Neurons Can Quickly Upregulate Glucose Transport Capacity Dumentioning

confidence: 99%

Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

J Cereb Blood Flow Metab

422

434

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Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-toblood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. Keywords: astrocyte; brain activation; glucose; lactate shuttling; metabolism; neuron Glucose is the major fuel for the brain, and its metabolism by different pathways has important functions related to energetics, neurotransmission, oxidation-reduction (redox) reactions, and biosynthesis of essential brain components (Figure 1). For many decades, lactate production in the brain was viewed as a consequence of inadequate oxygen delivery, disruption of oxidative metabolism, or mismatch between glycolytic and oxidative rates (Siesjö, 1978), but more recently, the conceptual role of lactate metabolism and function in the normal brain have undergone major changes, shifting from developmental fuel and glycolytic waste product to include its use as a supplemental fuel and signaling molecule. Starting in the 1970s to 1980s studies carried out in different laboratories with diverse experimental interests related to brain function brought attention to upregulation of glycolysis, lactate production, lactate release into the blood, the possibility of lactate shuttling among cell types within the brain, lactate fueling adult brain during exercise, and roles of lactate in the regulation of blood flow; some of these topics are controversial and highly debated. The experimental paradigm and physiologic status of subjects are critical for interpretation of data, and this review first presents a brief historical overview of studies related to brain lactate transport and metabolism, then compares sets of data to provide a perspective and context within which the consistency of simi...

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“…Uptake of the glucose analog 6-NBDG (Invitrogen) in NT2.N/A and NT2.A cultures was investigated using methods described by Waiza et al 27 Briefly, before measurement, culture medium was removed and the cells were washed with Krebs-Ringer HEPES buffer supplemented with 5 mmol/L glucose. Glucose in the medium was reduced to 0.5 mmol/L and the cells were incubated for 5 minutes.…”

Section: -Nbdg Uptake Assaymentioning

confidence: 99%

Functional Astrocyte-Neuron Lactate Shuttle in a Human Stem Cell-Derived Neuronal Network

Tarczyluk

Nagel

O’Neil

et al. 2013

J Cereb Blood Flow Metab

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The NT2.D1 cell line is one of the most well-documented embryocarcinoma cell lines, and can be differentiated into neurons and astrocytes. Great focus has also been placed on defining the electrophysiological properties of the neuronal cells, and more recently we have investigated the functional properties of their associated astrocytes. We now show for the first time that human stem cellderived astrocytes produce glycogen and that co-cultures of these cells demonstrate a functional astrocyte-neuron lactate shuttle (ANLS). The ANLS hypothesis proposes that during neuronal activity, glutamate released into the synaptic cleft is taken up by astrocytes and triggers glucose uptake, which is converted into lactate and released via monocarboxylate transporters for neuronal use. Using mixed cultures of NT2-derived neurons and astrocytes, we have shown that these cells modulate their glucose uptake in response to glutamate. Additionally, we demonstrate that in response to increased neuronal activity and under hypoglycaemic conditions, co-cultures modulate glycogen turnover and increase lactate production. Similar results were also shown after treatment with glutamate, potassium, isoproterenol, and dbcAMP. Together, these results demonstrate for the first time a functional ANLS in a human stem cell-derived co-culture.

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Glutamate Triggers Rapid Glucose Transport Stimulation in Astrocytes as Evidenced by Real-Time Confocal Microscopy

Cited by 234 publications

References 34 publications

Astrocytes generate Na ⁺ -mediated metabolic waves

Astrocytes generate Na ⁺ -mediated metabolic waves

Brain Lactate Metabolism: The Discoveries and the Controversies

Functional Astrocyte-Neuron Lactate Shuttle in a Human Stem Cell-Derived Neuronal Network

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Glutamate Triggers Rapid Glucose Transport Stimulation in Astrocytes as Evidenced by Real-Time Confocal Microscopy

Cited by 234 publications

References 34 publications

Astrocytes generate Na + -mediated metabolic waves

Astrocytes generate Na + -mediated metabolic waves

Brain Lactate Metabolism: The Discoveries and the Controversies

Functional Astrocyte-Neuron Lactate Shuttle in a Human Stem Cell-Derived Neuronal Network

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Product

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Astrocytes generate Na ⁺ -mediated metabolic waves

Astrocytes generate Na ⁺ -mediated metabolic waves