Glutamate Clearance Is Locally Modulated by Presynaptic Neuronal Activity in the Cerebral Cortex
Open accessAbstract
Excitatory amino acid transporters (EAATs) are abundantly expressed by astrocytes, rapidly remove glutamate from the extracellular environment, and restrict the temporal and spatial extent of glutamate signaling. Studies probing EAAT function suggest that their capacity to remove glutamate is large and does not saturate, even with substantial glutamate challenges. In contrast, we report that neuronal activity rapidly and reversibly modulates EAAT-dependent glutamate transport. To date, no physiological manipulation has shown changes in functional glutamate uptake in a nonpathological state. Using iGluSnFr-based glutamate imaging and electrophysiology in the adult mouse cortex, we show that glutamate uptake is slowed up to threefold following bursts of neuronal activity. The slowing of glutamate uptake depends on the frequency and duration of presynaptic neuronal activity but is independent of the amount of glutamate released. The modulation of glutamate uptake is brief, returning to normal within 50 ms after stimulation ceases. Interestingly, the slowing of glutamate uptake is specific to activated synapses, even within the domain of an individual astrocyte. Activity-induced slowing of glutamate uptake, and the increased persistence of glutamate in the extracellular space, is reflected by increased decay times of neuronal NR2A-mediated NMDA currents. These results show that astrocytic clearance of extracellular glutamate is slowed in a temporally and spatially specific manner following bursts of neuronal activity ≥30 Hz and that these changes affect the neuronal response to released glutamate. This suggests a previously unreported form of neuron–astrocyte interaction. SIGNIFICANCE STATEMENT We report the first fast, physiological modulation of astrocyte glutamate clearance kinetics. We show that presynaptic activity in the cerebral cortex increases the persistence of glutamate in the extracellular space by slowing its clearance by astrocytes. Because of abundant EAAT expression, glutamate clearance from the extracellular space has been thought to have invariant kinetics. While multiple studies report experimental manipulations resulting in altered EAAT expression, our findings show that astrocytic glutamate uptake is dynamic on a fast time-scale. This shows rapid plasticity of glutamate clearance, which locally modulates synaptic signaling in the cortex. As astrocytic glutamate uptake is a fundamental and essential mechanism for neurotransmission, this work has implications for neurotransmission, extrasynaptic receptor activation, and synaptic plasticity.
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Through GLAST, astroglia dynamically remove glutamate from the extracellular milieu, restricting its signaling activity in time and space and allowing for its recycling.
“Through the membrane glutamate aspartate transporter (GLAST), the astroglia dynamically remove glutamate from the extracellular milieu, restricting its signaling activity in time and space and allowing for its recycling [25, 30, 33].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [33]
The Introduction (page unavailable) says astrocytic transporters, including GLAST and GLT-1, rapidly remove extracellular glutamate and restrict signaling in time and space. The paper also reports dynamic modulation of clearance, but the cited passages attribute it to EAAT function generally, not specifically to GLAST, and do not address glutamate recycling. (LLM, conf=0.88)
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- Authors
- Armbruster, M., Hanson, E., & Dulla, C. G.
- Affiliations
- Tufts University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-10-05
- Volume
- 36
- Issue
- 40
- Pages
- 10404-10415
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5050332
- OpenAlex
- W2527796387
- Cited by
- 131
- References
- 56
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 20 · 2023: 7 · 2022: 14 · 2021: 19 · 2020: 15 · 2019: 11 · 2018: 17 · 2017: 9 · 2016: 2
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Epilepsy Foundation
- Center for Neuroscience Research (P30 NS047243)
- National Institute of Neurological Disorders and Stroke (T32NS061764, NS047243, R01NS076885, NS061764, P30NS047243, R56NS076885)
- 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 clearance, glutamate transporters, astrocytes, astrocyte-neuron interaction, cerebral cortex, synaptic plasticity, extrasynaptic receptors, glutamate imaging, iGluSnFR
- MeSH terms
- Animals, Astrocytes, Cerebral Cortex, Female, Male, Mice, Inbred C57BL, Neurons, Receptors, N-Methyl-D-Aspartate, Receptors, Presynaptic, Glutamic Acid, Excitatory Amino Acid Transporter 2, Mice, Electrophysiological Phenomena, In Vitro Techniques
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