A simulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain

Berg, C. J. Van den; Garfinkel, David

doi:10.1042/bj1230211

Cited by 382 publications

(184 citation statements)

References 23 publications

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“…Taking into account the 98-s time resolution and the sensitivity of the POCE experiment, we would not have detected the BC_ labeled fraction of glutamate that comprised a pool size less than =25% of the total concentration of cerebral glutamate or discerned glutamate turnover in a pool characterized by an exponential rate con stant faster than =0.33 min -I . Based on computer simulations of the kinetics of 14C labeling of amino acids and TCA cycle intermediates in the mouse brain from 14C-Iabeled glucose and acetate, Van den Berg and Garfinkel (1971) determined the flux to be = 1.25 j.1mol g -1 min -1 for the TCA cycle associ ated with the large glutamate pool (also see Hertz, 1979). Therefore, our results describing the turn over of the pool are compatible with estimated val ues of the rate of TCA cycle associated with the large (neuronal) pool of glutamate.…”

Section: Discussionmentioning

confidence: 99%

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy

Fitzpatrick

Hetherington

Behar

et al. 1990

J Cereb Blood Flow Metab

249

221

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Summary:The rate of incorporation of carbon from [1-13C]glucose into the and [3-CH21 of cerebral glutamate was measured in the rat brain in vivo by IH_ observed, 13C-edited (POCE) nuclear magnetic resonance (NMR) spectroscopy. Spectra were acquired every 98 s during a 6O-min infusion of [l-13C]glucose. Complete time courses were obtained from six animals. The measured intensity of the unresolved resonances of glu tamate and glutamine increased exponentially during the infusion and attained a steady state in -20 min with a first-order rate constant of 0. 130 ± 0.010 min -I (t1/2 = 5. 3 ± 0. 5 min). The appearance of the [3-13CH21 resonance in the POCE difference spectrum lagged behind that of the [4-13CH21 resonance and had not reached steady state at the end of the 60-min infusion (t1/2 = 26. 6 ± 4. 1 min). The increase observed in 13C-labeled glutamate represented isotopic enrichment and was not due to a change in the Cerebral glutamate functions as a neurotransmit ter, is necessary for cerebral ammonia detoxifica tion, and is directly related to cerebral energy me tabolism (see Cooper and Plum, 1987, and ref. therein). Glutamate metabolism occurs in at least two morphologically distinct cellular compartments (Hertz, 1979). A small, rapidly turning over pool of glutamate, thought to be the precursor of brain glu- 170 total glutamate concentration. The glucose infusion did not affect the levels of high-energy phosphates or intrac ellular pH as determined by 31p NMR spectroscopy. Since glucose carbon is incorporated into glutamate by rapid exchange with the tricarboxylic acid (TCA) cycle intermediate a-ketoglutarate, the rate of glutamate label ing provided an estimate of TCA cycle flux. We have determined the flux of carbon through the TCA cycle to be = 1.4 fLmol g -1 min -I. These experiments demon strate the feasibility of measuring metabolic fluxes in vivo using 13C-labeled glucose and the technique of 1 H observed, 13C-decoupled NMR spectroscopy. Key Words: Brain metabolism-[1-13C]Glucose-Glutamate Glycolysis-Nuclear magnetic resonance-Tricarboxylic acid cycle-Two-dimensional heteronuclear spectros copy.tamine, is located within the astrocytes. The pool of glutamate localized to the neurons is larger (at least 80% of total brain glutamate) and has a slower turn over rate than the astrocytic glutamate pool. Each glutamate pool is in equilibrium with a distinct tri carboxylic acid (TCA) cycle (Van den Berg et aI., 1969; Berl et aI., 1970). The flow of carbon from glucose to glutamate and the turnover time of the glutamate pool depend both on the rate of glycolysis and on the rate of entry of glucose carbon into the TCA cycle. Although turnover rates for glutamate have been estimated by radioactive tracer and sta ble isotope studies (Berl et aI., 1962(Berl et aI., , 1970 Cooper et aI., 1988) there has been no acceptable way to measure these rates in vivo.The turnover of cerebral glutamate and other me tabolites can be determined in vivo by monitoring the site-specific incorporation of l 3C using l 3C_ en...

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Section: Discussionmentioning

confidence: 99%

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy

Fitzpatrick

Hetherington

Behar

et al. 1990

J Cereb Blood Flow Metab

249

221

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“…The metabolism of GABA has been investigated with 13 C NMR (carbon nuclear magnetic resonance) spectroscopy in vitro (Waagepetersen et al, 1998) and in vivo (Patel et al, 2001), but owing to the difficulty in measuring the relative contributions of exogenous glutamate and glutamine to GABA synthesis, quantifications of the GABA-glutamine cycling flux found in the literature differ significantly. Recently, Yang et al (2007) found this flux to be one order of magnitude smaller than previously estimated (Van den Berg and Garfinkel, 1971;Patel et al, 2005). The still largely unknown metabolic interaction between astrocytes and GABAergic neurons adds to the challenge of understanding GABA metabolism and synthesis.…”

Section: Introductionmentioning

confidence: 93%

“…The source of glutamate precursors required for GABA synthesis has been extensively investigated in vivo and in vitro for more than 30 years, following a pioneering work by Van den Berg and Garfinkel (1971), who, using a multicompartment mathematical model, identified glutamine as a possible precursor of glutamate and proposed cycling of GABA and glutamine between astrocytes and neurons. The interest in GABA precursors was motivated by the lack of pyruvate carboxylase (PC) in neurons, which implied that the loss of GABA released during neurotransmission should be compensated by the flow of a precursor in the opposite direction (Bak et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Energetics of Inhibition: Insights with a Computational Model of the Human GABAergic Neuron–Astrocyte Cellular Complex

Occhipinti

Somersalo

Calvetti

2010

J Cereb Blood Flow Metab

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We investigate metabolic interactions between astrocytes and GABAergic neurons at steady states corresponding to different activity levels using a six-compartment model and a new methodology based on Bayesian statistics. Many questions about the energetics of inhibition are still waiting for definite answers, including the role of glutamine and lactate effluxed by astrocytes as precursors for c-aminobutyric acid (GABA), and whether metabolic coupling applies to the inhibitory neurotransmitter GABA. Our identification and quantification of metabolic pathways describing the interaction between GABAergic neurons and astrocytes in connection with the release of GABA makes a contribution to this important problem. Lactate released by astrocytes and its neuronal uptake is found to be coupled with neuronal activity, unlike glucose consumption, suggesting that in astrocytes, the metabolism of GABA does not require increased glycolytic activity. Negligible glutamine trafficking between the two cell types at steady state questions glutamine as a precursor of GABA, not excluding glutamine cycling as a transient dynamic phenomenon, or a prominent role of GABA reuptake. Redox balance is proposed as an explanation for elevated oxidative phosphorylation and adenosine triphosphate hydrolysis in astrocytes, decoupled from energy requirements.

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“…This glutamate-glutamine cycle between cell types is central to normal brain function and the rate of this cycle is indicative of glutamatergic activity. 56 Thus, a decrease in the glutamate/glutamine ratio may indicate that valproate elicits a general change in glutamatergic activity in the brain. This potential change in glutamate/glutamine cycling would counter the result in the post-mortem brain analysis that found increased levels of glutamate in bipolar samples.…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 99%

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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A simulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain

Cited by 382 publications

References 23 publications

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy

Energetics of Inhibition: Insights with a Computational Model of the Human GABAergic Neuron–Astrocyte Cellular Complex

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

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A simulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain

Cited by 382 publications

References 23 publications

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by 1-Observed, 13C-Edited NMR Spectroscopy

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by 1-Observed, 13C-Edited NMR Spectroscopy

Energetics of Inhibition: Insights with a Computational Model of the Human GABAergic Neuron–Astrocyte Cellular Complex

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

Contact Info

Product

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About

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by ¹-Observed, ¹³C-Edited NMR Spectroscopy