Glial Glutamate Transporters Mediate a Functional Metabolic Crosstalk between Neurons and Astrocytes in the Mouse Developing Cortex

Voutsinos-Porche, Brigitte; Bonvento, Gilles; Tanaka, Kohichi; Steiner, Pascal; Welker, Egbert; Chatton, Jean–Yves; Magistretti, Pierre J.; Pellerin, Luc

doi:10.1016/s0896-6273(02)01170-4

Cited by 267 publications

(219 citation statements)

References 46 publications

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“…The uptake of neuronally released glutamate and GABA by astroglia is also functional by this time (Vitellaro-Zuccarello et al, 2003). The expression of glial glutamate transporters and glutamine synthetase increase in parallel, reaching B70% to 80% of their adult values by P10 (Voutsinos-Porche et al, 2003). Functional coupling between glutamatergic neurons and astro-glia, in terms of glial glutamate transport-coupled, 2-deoxyglucose uptake, has been demonstrated in vitro for mouse P10 somatosensory cortex (Voutsinos-Porche et al, 2003), which is similar to that seen in the adult.…”

Section: Structure Of the Metabolic Modelsupporting

confidence: 58%

“…It is significant that this pattern of 'functional' glucose use in the cortex is not seen for ketone bodies (Auestad et al, 1990;Nehlig and Pereira de Vasconcelos, 1993), where utilization remains homogeneous and declines rapidly after weaning. These findings suggest that glucose (and glycolysis) supports a critical function(s) in the expression of developing neural activity (Novotny et al, 2001;Takagaki, 1974;Voutsinos-Porche et al, 2003) not provided by other fuels.…”

Section: Introductionmentioning

confidence: 90%

“…Glutamate and potassiumevoked increases in respiration are not observed in rat brain slices before P10 (Takagaki, 1974). In 10-day-old mice, the stimulation-induced increase in 2-14 C-deoxyglucose uptake in the barrel cortex during whisker deflection is substantially suppressed with mutations or antisense knockdown of the glial glutamate transporters, GLAST or GLT1 (Voutsinos-Porche et al, 2003). This mechanism could explain the apparent specificity of glucose in the attainment of neurological competence in the postnatal period.…”

Section: Introductionmentioning

confidence: 93%

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Glutamatergic and GABAergic Neurotransmitter Cycling and Energy Metabolism in Rat Cerebral Cortex during Postnatal Development

Chowdhury

Patel

Mason

et al. 2007

J Cereb Blood Flow Metab

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The contribution of glutamatergic and c-aminobutyric acid (GABA)ergic neurons to oxidative energy metabolism and neurotransmission in the developing brain is not known. Glutamatergic and GABAergic fluxes were assessed in neocortex of postnatal day 10 (P10) and 30 (P30) urethaneanesthetized rats infused intravenously with [1,6-13 C 2 ]glucose for different time intervals (time course) or with [2-13 C]acetate for 2 to 3 h (steady state). Amino acid levels and 13 C enrichments were determined in tissue extracts ex vivo using 1 H-[ 13 C]-NMR spectroscopy. Metabolic fluxes were estimated from the best fits of a three-compartment metabolic model (glutamatergic neurons, GABAergic neurons, and astroglia) to the 13 C-enrichment time courses of amino acids from [1,6-13 C 2 ]glucose, constrained by the ratios of neurotransmitter cycling (V cyc )-to-tricarboxylic acid (TCA) cycle flux (V TCAn ) calculated from the steady-state [2-13 C]acetate enrichment data. From P10 to P30 increases in total neuronal (glutamate plus GABA) TCA cycle flux (3¾; 0.2460.05 versus 0.716 0.07 lmol per g per min, P < 0.0001) and total neurotransmitter cycling flux (3.1 to 5¾; 0.07 to 0.11 (6 0.03) versus 0.3460.03 lmol per g per min, P < 0.0001) were approximately proportional. Incremental changes in total cycling (DV cyc(tot) ) and neuronal TCA cycle flux (DV TCAn(tot) ) between P10 and P30 were 0.23 to 0.27 and 0.47 lmol per g per min, respectively, similar to the B1:2 relationship previously reported for adult cortex. For the individual neurons, increases in V TCAn and V cyc were similar in magnitude (glutamatergic neurons, 2.7¾ versus 2.8 to 4.6¾; GABAergic neurons, B5¾ versus B7¾), although GABAergic flux changes were larger. The findings show that glutamate and GABA neurons undergo large and approximately proportional increases in neurotransmitter cycling and oxidative energy metabolism during this major postnatal growth spurt.

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Section: Structure Of the Metabolic Modelsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 93%

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Glutamatergic and GABAergic Neurotransmitter Cycling and Energy Metabolism in Rat Cerebral Cortex during Postnatal Development

Chowdhury

Patel

Mason

et al. 2007

J Cereb Blood Flow Metab

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“…We found that the increase in FDG uptake during QA injection was significantly higher in the lenti-CNTF group. It has been proposed that glutamate uptake by glial transporters, which accounts for 80% of total uptake in the striatum (Rothstein et al, 1996), is coupled to glucose uptake from blood stream (Pellerin and Magistretti, 1994;Voutsinos-Porche et al, 2003) by a stoichiometry close to 1:1 (Sibson et al, 1998). Therefore, the higher FDG uptake during QA injection in the lenti-CNTF group may reflect an enhanced glutamate uptake by activated astrocytes.…”

Section: Cntf Improves Glutamate Handling and Energy Supplymentioning

confidence: 99%

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

Escartin¹,

Brouillet²,

Gubellini³

et al. 2006

J. Neurosci.

111

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To study the functional role of activated astrocytes in glutamate homeostasis in vivo, we used a model of sustained astrocytic activation in the rat striatum through lentiviral-mediated gene delivery of ciliary neurotrophic factor (CNTF). CNTF-activated astrocytes were hypertrophic, expressed immature intermediate filament proteins and highly glycosylated forms of their glutamate transporters GLAST and GLT-1. CNTF overexpression produced a redistribution of GLAST and GLT-1 into raft functional membrane microdomains, which are important for glutamate uptake. In contrast, CNTF had no detectable effect on the expression of a number of neuronal proteins and on the spontaneous glutamatergic transmission recorded from striatal medium spiny neurons. These results were replicated in vitro by application of recombinant CNTF on a mixed neuron/astrocyte striatal culture. Using microdialysis in the rat striatum, we found that the accumulation of extracellular glutamate induced by quinolinate (QA) was reduced threefold with CNTF. In line with this result, CNTF significantly increased QA-induced [ 18 F]-fluoro-2-deoxyglucose uptake, an indirect index of glutamate uptake by astrocytes. Together, these data demonstrate that CNTF activation of astrocytes in vivo is associated with marked phenotypic and molecular changes leading to a better handling of increased levels of extracellular glutamate. Activated astrocytes may therefore be important prosurvival agents in pathological conditions involving defects in glutamate homeostasis.

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“…Shulman et al (2001b) suggested that 80% of energy use is correlated with glutamate passing through the glutamate-glutamine cycle and, therefore, excitatory active signaling processes ( [Sibson et al, 1998] and [Shen et al, 1999]). Astrocyte glutamate transporters have been proposed to coordinate Glc and O 2 usage in the central nervous system, linking energy production to synaptic glutamate release ( [Magistretti and Pellerin, 1999a], [Magistretti and Pellerin, 1999b] and [Voutsinos-Porche et al, 2003]). In this context, it is also important to note that glutamate taken up by astrocytes is not only converted to glutamine.…”

Section: The Energy Budget For Cellular Workmentioning

confidence: 99%

The micro-architecture of the cerebral cortex: Functional neuroimaging models and metabolism

et al. 2008

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In order to interpret/integrate data obtained with different functional neuroimaging modalities (e.g. fMRI, EEG/MEG, PET/SPECT, fNIRS), forward-generative models of a diversity of brain mechanisms at the mesoscopic level are considered necessary. For the cerebral cortex, the brain structure with possibly the most relevance for functional neuroimaging, a variety of such biophysical models has been proposed over the last decade. The development of technological tools to investigate in vitro the physiological, anatomical and biochemical principles at the microscopic scale in comparative studies formed the basis for such theoretical progresses. However, with the most recent introduction of systems to record electrical (e.g. miniaturized probes chronically/acutely implantable in the brain), optical (e.g. two-photon laser scanning microscopy) and atomic nuclear spectral (e.g. nuclear magnetic resonance spectroscopy) signals using living laboratory animals, the field is receiving even greater attention. Major advances have been achieved by combining such sophisticated recording systems with new experimental strategies (e.g. transgenic/knock-out animals, high resolution stereotaxic manipulation systems for probe-guidance and cellular-scale chemical-delivery). Theoreticians may now be encouraged to re-consider previously formulated mesoscopic level models in order to incorporate important findings recently made at the microscopic scale. In this series of reviews, we summarize the background at the microscopic scale, which we suggest will constitute the foundations for upcoming representations at the mesoscopic level. In this first part, we focus our attention on the nerve ending particles in order to summarize basic principles and mechanisms underlying cellular metabolism in the cerebral cortex. It will be followed by two parts highlighting major features in its organization/working-principles to regulate both cerebral blood circulation and neuronal activity, respectively. Contemporary theoretical models for functional neuroimaging will be revised in the fourth part, with particular emphasis in their applications, advantages/limitations and future prospects. However, a wide range of neuroimaging methods have been routinely used to map taskinduced changes in the neuronal activity indirectly reflected in variations of the local 1 BOLD signal calibration by hyperoxia requires additionally measuring PaO2 (partial pressure of oxygen in arterial blood). HHS Public Access Riera et al. Page 2Neuroimage. Author manuscript; available in PMC 2015 March 03. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript cerebral perfusion (i.e. functional hyperemia). For many years now, researchers have been trying to elucidate the basic principles underlying this phenomenon and several hypotheses have been formulated so far (see a review by Iadecola 2004). From them the metabolic and neurogenic hypotheses, which arise from answering the question of whether this phenomenon is entirely due to a metabolic deficit or i...

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Glial Glutamate Transporters Mediate a Functional Metabolic Crosstalk between Neurons and Astrocytes in the Mouse Developing Cortex

Cited by 267 publications

References 46 publications

Glutamatergic and GABAergic Neurotransmitter Cycling and Energy Metabolism in Rat Cerebral Cortex during Postnatal Development

Glutamatergic and GABAergic Neurotransmitter Cycling and Energy Metabolism in Rat Cerebral Cortex during Postnatal Development

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

The micro-architecture of the cerebral cortex: Functional neuroimaging models and metabolism

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