Extracellular glutamate: functional compartments operate in different concentration ranges
Open accessAbstract
Extracellular glutamate of glial origin modulates glial and neuronal glutamate release and synaptic plasticity. Estimates of the tonic basal concentration of extracellular glutamate range over three orders of magnitude (0.02-20 μM) depending on the technology employed to make the measurement. Based upon binding constants for glutamate receptors and transporters, this range of concentrations translates into distinct physiological and pathophysiological roles for extracellular glutamate. Here we speculate that the difference in glutamate measurements can be explained if there is patterned membrane surface expression of glutamate release and transporter sites creating extracellular subcompartments that vary in glutamate concentration and are preferentially sampled by different technologies.
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50 μM and 1 mM glutamate approximately represent extrasynaptic and active synaptic glutamate levels, respectively.
“Notably, 50 μM and 1 mM glutamate roughly estimate extrasynaptic and active synaptic glutamate levels, respectively”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Moussawi et al., 2011
The Abstract says glutamate in the synaptic cleft exceeds 1 mM briefly after action-potential-mediated release, supporting the active-synaptic estimate. But it gives 0.02–30 μM for extracellular glutamate outside the cleft, while the section on in vivo measurements identifies a tonic pool of 1–5 μM; neither supports 50 μM as a rough extrasynaptic level. Page numbers are unavailable in our copy. (LLM, conf=0.91)
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Scofield, M. D., Boger, H. A., Smith, R. J., Li, H., Haydon, P. G., & Kalivas, P. W. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.02.016 · Cited by 197 · see citing works
Self-citationPham, T. H., & Gardier, A. M. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.02.017 · Cited by 186 · see citing works
Mechanisms of ketamine and its metabolites as antidepressants
Hess, E. M., Riggs, L. M., Michaelides, M., & Gould, T. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114892 · Cited by 169 · see citing works
Glutamate transport: a new bench to bedside mechanism for treating drug abuse
Spencer, S., & Kalivas, P. W. (2017) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx050 · Cited by 71 · see citing works
Self-citationZhang, G., Cinalli, D., Cohen, S. J., Knapp, K. D., Rios, L. M., Martínez-Hernández, J., Luján, R., & Stackman, R. W. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.04.033 · Cited by 41 · see citing works
Heterodimer of A2A and oxytocin receptors regulating glutamate release in adult striatal astrocytes
Amato, S., Averna, M., Guidolin, D., Pedrazzi, M., Pelassa, S., Capraro, M., Passalacqua, M., Bozzo, M., Gatta, E., Anderlini, D., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042326 · Cited by 23 · see citing works
Imaging Approaches for the Study of Metabolism in Real Time Using Genetically Encoded Reporters
Chandris, P., Giannouli, C. C., & Panayotou, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.725114 · Cited by 19 · see citing works
- Authors
- Moussawi, K., Riegel, A., Nair, S., & Kalivas, P. W.
- Affiliations
- Medical University of South Carolina (US)
- University of Missouri (US)
- Corresponding author
- Kalivas, Peter W.
- Venue
- Frontiers in Systems Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2011
- Volume
- 5
- Pages
- 94-94
- ISSN
- 1662-5137 (ISSN-L)
- PMC
- PMC3254064
- OpenAlex
- W2095780210
- Cited by
- 184
- References
- 101
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 6 · 2023: 13 · 2022: 20 · 2021: 16 · 2020: 14 · 2019: 25 · 2018: 15 · 2017: 15 · 2016: 12 · 2015: 11 · 2014: 6 · 2013: 6 · 2012: 4
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Systems Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (DA015369)
- National Institute on Drug Abuse (R37DA003906, R01DA012513, P50DA015369, R01DA003906, R01DA033342)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- extracellular glutamate, glutamate release, glutamate transporters, glutamate receptors, binding constant, synaptic plasticity, neuron-glia interactions
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