Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons
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Although the role of astrocyte glutamate transporters in glutamate clearance is well illustrated, the role of glutamine synthetase (GS) that influences this process remains to be elucidated. We examined whether GS affected the uptake of glutamate in astrocytes in vitro. The glutamate uptake was assessed by measuring the concentration of glutamate and glutamine in culture medium in the presence or absence of glutamate. We demonstrated that inhibition of GS in astrocytes by MSO significantly impaired glutamate uptake and glutamine release. Conversely, induction of GS expression in astrocytes by gene transfer significantly enhanced the glutamate uptake and glutamine release. When an inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was applied to the cultures, it significantly reduced GS expression and inhibited glutamate-induced GS activation resulting in increased excitotoxicity to neurons. These results suggest that GS in astrocytes may represent a novel target for neuroprotection against neuronal dysfunction and death that occur in many neurological disorders.
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When a large amount of glutamate is released from neuronal vesicles, glutamate clearance is mainly achieved by glutamate transporters on the membrane of astrocytes, which transport excess glutamate into astrocytes, where it is converted to glutamylamine through the action of glutamine synthase, reducing damage to neurons.
“When a large amount of glutamate is released from neuronal vesicles, glutamate clearance is mainly achieved by glutamate transporters (EAATs) on the membrane of astrocytes, which transport excess glutamate into astrocytes, where it is converted to glutamylamine through the action of glutamine synthase, reducing damage to neurons. 88 , 89”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [89]
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- Authors
- Zou, J., Wang, Y.-X., Dou, F.-F., Lü, H.-Z., Ma, Z.-W., Lu, P.-H., & Xu, X.-M.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Lu, Pei-Hua
- Xu, Xiao-Ming
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 56
- Issue
- 4
- Pages
- 577-584
- ISSN
- 0197-0186 (ISSN-L)
- PMC
- PMC2831119
- OpenAlex
- W2070004275
- Cited by
- 181
- References
- 47
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 10 · 2020: 16 · 2019: 10 · 2018: 9 · 2017: 11 · 2016: 16 · 2015: 14 · 2014: 12 · 2013: 16 · 2012: 9
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health (7r01ns050243-06)
- National Institute of Neurological Disorders and Stroke (R01NS111776, NS52290, R01NS059622, R01NS052290, R01-NS050243, R01NS036350, NS36350, NS50243)
- 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
- glutamine synthetase, astrocytes, glutamate excitotoxicity, glutamate uptake, glutamine release, glutamate transporters, glutamate clearance, TNF-α, neuroprotection, gene transfer, neuronal cell death
- MeSH terms
- Animals, Astrocytes, Cell Survival, Cells, Cultured, Glutamate-Ammonia Ligase, Nerve Degeneration, Neurons, Plasmids, Transfection, Tumor Necrosis Factor-alpha, Blotting, Western, Down-Regulation, Rats, Sprague-Dawley, Apoptosis, Glutamic Acid, Excitatory Amino Acids, Rats
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