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In Vivo Nuclear Magnetic Resonance Studies of Glutamate--Aminobutyric Acid-Glutamine Cycling in Rodent and Human Cortex: the Central Role of Glutamine^{1 ,2}

Kevin L. Behar^*3 and Douglas L. Rothman

Departments of ^* Psychiatry and Diagnostic Radiology, Magnetic Resonance Center for Research in Metabolism and Physiology, Yale University School of Medicine, New Haven, CT 06520

³To whom correspondence should be addressed. E-mail: Kevin.behar{at}yale.edu.

It has been recognized for many years that the metabolism of brain glutamate and -aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters, is linked to a substrate cycle between neurons and astrocytes involving glutamine. However, the quantitative significance of these fluxes in vivo was not known. Recent in vivo ¹³C and ¹⁵N NMR studies in rodents and ¹³C NMR in humans indicate that glutamine synthesis is substantial and that the total glutamate-GABA-glutamine cycling flux, necessary to replenish neurotransmitter glutamate and GABA, accounts for >80% of net glutamine synthesis. In studies of the rodent cortex, a linear relationship exists between the rate of glucose oxidation and total glutamate-GABA-glutamine cycling flux over a large range of cortical electrical activity. The molar stoichiometric relationship (1:1) found between these fluxes suggests that they share a common mechanism and that the glutamate-GABA-glutamine cycle is coupled to a major fraction of cortical glucose utilization. Thus, glutamine appears to play a central role in the normal functional energetics of the cerebral cortex.

KEY WORDS: • glutamine • glutamate-glutamine cycle • neuron • astrocyte trafficking • NMR • cerebral glucose utilization

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