In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function
Abstract
Until very recently, non-invasive measurement of the glutamate-glutamine cycle in the intact mammalian brain had not been possible. In this review, we describe some studies that have led to quantitative assessment of the glutamate-glutamine cycle (Vcyc), as well as other important metabolic fluxes (e.g., glucose oxidation, CMRglc(ox)), with (13)C magnetic resonance spectroscopy (MRS) in vivo. These (13)C MRS studies clearly demonstrate that glutamate released from presynaptic neurons is taken up by the astrocyte for subsequent glutamine synthesis. Contrary to the earlier concept of a small, metabolically inactive neurotransmitter pool, in vivo (13)C MRS studies demonstrate that glutamate release and recycling is a major metabolic pathway that cannot be distinguished from its actions of neurotransmission. Furthermore, the in vivo (13)C MRS studies demonstrate in the rat cerebral cortex that increases in Vcyc and neuronal CMRglc(ox) are linearly related with a close to 1:1 slope. Measurements in human cerebral cortex are in agreement with this result. This relationship is consistent with more than two thirds of the energy yielded by glucose oxidation being used to support events associated with glutamate neurotransmission, and it supports a molecular model of a stoichiometric coupling between glutamate neurotransmission and functional glucose oxidation. (13)C MRS measurements of resting human cerebral cortex have found a high level of glutamate-glutamine cycling. This high resting neuronal activity, which is subtracted away in brain mapping studies by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has significant implications for the interpretations of functional imaging data. Here we review and discuss the importance of neurotransmission and neuroenergetics as measured by (13)C MRS for understanding brain function and interpreting fMRI.
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The glutamatergic transmission and metabolism are strongly coupled, and findings on glutamate and glutamine levels in schizophrenia could give insight into possible changes in neuronal activity during the course of the disease.
“Theglutamatergictransmission and metabolism are strongly coupled, and findings on glutamate and glutamine levels in schizophrenia could give an insight in possible changes in neuronal activity during the course of the disease.21”
From Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies (2013) · cites this paper as [21]
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Self-citationShen, J., Sibson, N. R., Cline, G. W., Behar, K. L., Rothman, D. L., & Shulman, R. G. (1998) · Developmental Neuroscience · doi:10.1159/000017341 · Cited by 66 · see citing works
Self-citationConti, F., & Minelli, A. (1994) · Journal of Histochemistry & Cytochemistry · doi:10.1177/42.6.7910617 · Cited by 66 · see citing works
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In vitro and ex vivo 13C-NMR Spectroscopy Studies of Pyruvate Recycling in Brain
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[1‐ 13 C] glucose MRS in chronic hepatic encephalopathy in man
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Turnover of human muscle glycogen with low-intensity exercise
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Measurement of brain oxygen utilization with radioactive oxygen-15: experimental verification
Raichle, M. E., Grubb, R. L., Eichling, J. O., et al. (1976) · Journal of Applied Physiology · doi:10.1152/jappl.1976.40.4.638 · Cited by 41 · see citing works
Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy
van Zijl, P. C. M., Davis, D., Eleff, S. M., MOONEN, C. T. W., Parker, R., & Strong, J. M. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.6.e1216 · Cited by 41 · see citing works
Kida, I., Hyder, F., & Behar, K. L. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200105000-00013 · Cited by 40 · see citing works
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New Approaches to Functional Neuroenergetics
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What you see is what you think – or is it?
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Wheeler-Kingshott (2000) · doi:10.1002/1522-2594(200011)44:5
Slow vasomotor fluctuation in fMRI of anesthetized child brain
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Sleep function and synaptic homeostasis
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Activity-dependent regulation of energy metabolism by astrocytes: an update
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Self-citationSmart, K., Liu, H., Matuskey, D., Chen, M.-K., Torres, K., Nabulsi, N., Labaree, D., Ropchan, J., Hillmer, A. T., Huang, Y., et al. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20946198 · Cited by 42 · see citing works
- Authors
- Rothman, D. L., Behar, K. L., Hyder, F., & Shulman, R. G.
- Affiliations
- Yale University (US)
- Venue
- Annual Review of Physiology
- Publisher
- Annual Reviews
- Published
- 2003-03
- Volume
- 65
- Issue
- 1
- Pages
- 401-427
- ISSN
- 0066-4278 (ISSN-L)
- 1545-1585
- OpenAlex
- W2158402798
- Cited by
- 337
- References
- 122
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 7 · 2023: 5 · 2022: 22 · 2021: 14 · 2020: 18 · 2019: 16 · 2018: 18 · 2017: 12 · 2016: 10 · 2015: 13 · 2014: 15 · 2013: 19 · 2012: 21
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29ns037203-05)
- National Institute on Deafness and Other Communication Disorders (DC-003710, R01DC003710)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 27121, R01DK027121)
- National Institute of Neurological Disorders and Stroke (NS 32126, R29NS032126, NS34813, NS37203, NS-044594, R01NS034813)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD032573, HD32573)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamate-glutamine cycle, glutamatergic neurotransmission, neuroenergetics, 13C NMR, presynaptic glutamate release, resting-state brain activity, cerebral cortex, brain energy metabolism
- MeSH terms
- Animals, Brain, Cell Communication, Energy Metabolism, Humans, Neuroglia, Neurons, Magnetic Resonance Spectroscopy, Glutamic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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