Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate
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Three glutamate transporters have been identified in rat, including astroglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1. Here we demonstrate that inhibition of the synthesis of each glutamate transporter subtype using chronic antisense oligonucleotide administration, in vitro and in vivo, selectively and specifically reduced the protein expression and function of glutamate transporters. The loss of glial glutamate transporters GLAST or GLT-1 produced elevated extracellular glutamate levels, neurodegeneration characteristic of excitotoxicity, and a progressive paralysis. The loss of the neuronal glutamate transporter EAAC1 did not elevate extracellular glutamate in the striatum but did produce mild neurotoxicity and resulted in epilepsy. These studies suggest that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.
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Downregulation of EAAT1 could induce hyperactivation of the surrounding neuronal network due to a failure to efficiently terminate excitatory synaptic signalling.
“Such a change could induce hyperactivation of the surrounding neuronal network due to a failure to efficiently terminate excitatory synaptic signalling42.”
From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [42]
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- Authors
- Rothstein, J. D., Dykes-Hoberg, M., Pardo, C. A., Bristol, L. A., Jin, L., Kuncl, R. W., Kanai, Y., Hediger, M. A., Wang, Y., Schielke, J. P., & Welty, D. F.
- Affiliations
- Johns Hopkins University (US)
- Kyorin University (JP)
- Brigham and Women's Hospital (US)
- Corresponding author
- Rothstein, Jeffrey D
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1996-03
- Volume
- 16
- Issue
- 3
- Pages
- 675-686
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2128744963
- Cited by
- 2,534
- References
- 0
- Citations by year
- 2026: 49 · 2025: 41 · 2024: 63 · 2023: 69 · 2022: 74 · 2021: 76 · 2020: 80 · 2019: 68 · 2018: 70 · 2017: 68 · 2016: 98 · 2015: 103 · 2014: 116 · 2013: 112 · 2012: 98
- FWCI
- 33.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health
- National Institute on Aging (AG 12992, P01AG012992)
- National Institute of Neurological Disorders and Stroke (NS 33958, R01NS033958)
- 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
- glutamate transporters, GLAST, GLT-1, EAAC1, excitotoxicity, glutamate clearance, antisense oligonucleotides, neurodegeneration, extracellular glutamate, epilepsy, progressive paralysis, striatum
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Glutamates, Hippocampus, Immunohistochemistry, Male, Microscopy, Electron, Spinal Cord, Gene Expression, Oligonucleotides, Antisense, Rats, Sprague-Dawley, ATP-Binding Cassette Transporters, Amino Acid Transport System X-AG, Rats
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