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Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain

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Abstract

Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid, the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.

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Abbreviations

AKG:

α-Ketoglutarate

ALAT:

Alanine aminotransferase

Aralar/AGC1:

Aspartate-glutamate carrier

BCAT:

Branched-chain aminotrasferases

BCKDC:

Branched-chain keto acid dehydrogenase complex

cAAT:

Cytosolic aspartate amino-transferase

cME:

Cytosolic malic enzyme

CS:

Citrate synthase

DIC:

Dicarboxylate carrier

EAAT:

Excitatory amino acids transporter

GABA:

γ-Aminobutyric acid

GAD:

Glutamate decarboxylase

GC:

Glutamate/hydroxyl carrier

GCL:

Glutamate-cysteine ligase

GDH:

Glutamate dehydrogenase

GS:

Glutamine synthetase

mAAT:

Mitochondrial aspartate amino-transferase

MAS:

Malate-aspartate shuttle

MCT:

Monocarboxylate transporter

mME:

Mitochondrial malic enzyme

OAA:

Oxalacetate

PAG:

Phosphate-activated glutaminase

PC:

Pyruvate carboxylase

PEPCK:

Phosphoenolpyruvate-carboxykinase

TCA:

Tricarboxylic acid

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Acknowledgments

S. M. thanks the grant NIH R01 DK62440 for support. This project was also supported by the National Center for Research Resources (Grant Number P41 RR008079) and the National Institute of Biomedical Imaging and Bioengineering (Grant Number P41 EB015894) of NIH. Additional funding supports to CMRR are: Minnesota Medical Foundation, and P30 NS057091. This work was finally supported by the NIH grant 1UL1RR033183 and KL2 RR033182 from the National Center for Research Resources (NCRR) to the University of Minnesota Clinical and Translational Science Institute (CTSI).

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Authors and Affiliations

  1. Department of Radiology, Center for Magnetic Resonance Research, University of Minnesota, 2021 6th St. S.E., Minneapolis, MN, USA

    Silvia Mangia

  2. MARBILab, Museo storico della fisica e Centro di studi e ricerche “Enrico Fermi”, Rome, Italy

    Federico Giove & Mauro DiNuzzo

  3. Department of Physics, University of Rome “La Sapienza”, Rome, Italy

    Federico Giove & Mauro DiNuzzo

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  1. Silvia Mangia
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  2. Federico Giove
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  3. Mauro DiNuzzo
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Correspondence to Silvia Mangia.

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Special Issue: In Honor of Leif Hertz.

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Mangia, S., Giove, F. & DiNuzzo, M. Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain. Neurochem Res 37, 2554–2561 (2012). https://doi.org/10.1007/s11064-012-0848-4

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