1. ¹Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA
2. ²Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA
3. ³Division of Bioimaging Sciences (DBS), Yale University School of Medicine, New Haven, Connecticut, USA
4. ⁴Magnetic Resonance Research Center (MRRC), Yale University School of Medicine, New Haven, Connecticut, USA
5. ⁵Quantitative Neuroscience with Magnetic Resonance (QNMR), Yale University School of Medicine, New Haven, Connecticut, USA
6. ⁶Pathophysiology and Experimental Tomography Center, Aarhus University Hospitals, Aarhus University, Aarhus, Denmark
7. ⁷Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence: Dr F Hyder, N143 TAC (MRRC), 300 Cedar Street, Yale University, New Haven, Connecticut 06510, USA. E-mail: fahmeed.hyder@yale.edu

Received 16 August 2005; Accepted 31 October 2005; Published online 11 January 2006.

Abstract

Prior ¹³C magnetic resonance spectroscopy (MRS) experiments, which simultaneously measured in vivo rates of total glutamate–glutamine cycling (V_cyc(tot)) and neuronal glucose oxidation (CMR_glc(ox), N), revealed a linear relationship between these fluxes above isoelectricity, with a slope of 1. In vitro glial culture studies examining glutamate uptake indicated that glutamate, which is cotransported with Na⁺, stimulated glial uptake of glucose and release of lactate. These in vivo and in vitro results were consolidated into a model: recycling of one molecule of neurotransmitter between glia and neurons was associated with oxidation of one glucose molecule in neurons; however, the glucose was taken up only by glia and all the lactate (pyruvate) generated by glial glycolysis was transferred to neurons for oxidation. The model was consistent with the 1:1 relationship between CMR_glc(ox), N and V_cyc(tot) measured by ¹³C MRS. However, the model could not specify the energetics of glia and -amino butyric acid (GABA) neurons because quantitative values for these pathways were not available. Here, we review recent ¹³C and ¹⁴C tracer studies that enable us to include these fluxes in a more comprehensive model. The revised model shows that glia produce at least 8% of total oxidative ATP and GABAergic neurons generate 18% of total oxidative ATP in neurons. Neurons produce at least 88% of total oxidative ATP, and take up 26% of the total glucose oxidized. Glial lactate (pyruvate) still makes the major contribution to neuronal oxidation, but 30% less than predicted by the prior model. The relationship observed between CMR_glc(ox), N and V_cyc(tot) is determined by glial glycolytic ATP as before. Quantitative aspects of the model, which can be tested by experimentation, are discussed.