The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [33]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Glutamate neurotoxicity and diseases of the nervous system
Choi, D. W. (1988) · Neuron · doi:10.1016/0896-6273(88)90162-6 · Cited by 8,188
Danbolt, N. C. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00067-8 · Cited by 4,227
Advanced methods of microscope control using μManager software
Edelstein, A., Tsuchida, M. A., Amodaj, N., Pinkard, H., Vale, R. D., & Stuurman, N. (2014) · Journal of Biological Methods · doi:10.14440/jbm.2014.36 · Cited by 1,927
Epilepsy and Exacerbation of Brain Injury in Mice Lacking the Glutamate Transporter GLT-1
Tanaka, K., Watase, K., Manabe, T., Yamada, K., Watanabe, M., Takahashi, K., Iwama, H., Nishikawa, T., Ichihara, N., Kikuchi, T., et al. (1997) · Science · doi:10.1126/science.276.5319.1699 · Cited by 1,755
Localization of neuronal and glial glutamate transporters
Rothstein, J. D., Martin, L. J., Levey, A. I., Dykes‐Hoberg, M., Jin, L., Wu, D. M., Nash, N. R., & Kuncl, R. W. (1994) · Neuron · doi:10.1016/0896-6273(94)90038-8 · Cited by 1,703
β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression
Rothstein, J. D., Patel, S., Regan, M. R., Haenggeli, C., Huang, Y. H., Bergles, D. E., Jin, L., Dykes Hoberg, M., Vidensky, S., Chung, D. S., et al. (2005) · Nature · doi:10.1038/nature03180 · Cited by 1,518
Orkand, R. K., Nicholls, J. G., & Kuffler, S. W. (1966) · Journal of Neurophysiology · doi:10.1152/jn.1966.29.4.788 · Cited by 1,213
Quinoxalinediones: Potent Competitive Non-NMDA Glutamate Receptor Antagonists
Honoré, T., Davies, S. N., Drejer, J., Fletcher, E. J., Jacobsen, P., Lodge, D., & Nielsen, F. (1988) · Science · doi:10.1126/science.2899909 · Cited by 1,191
The Time Course of Glutamate in the Synaptic Cleft
Clements, J. D., Lester, R. A. J., Tong, G., Jahr, C. E., & Westbrook, G. L. (1992) · Science · doi:10.1126/science.1359647 · Cited by 1,089
Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex
Arriza, J. L., Fairman, W. A., Wadiche, J. I., Murdoch, G., Kavanaugh, M. P., & Amara, S. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-09-05559.1994 · Cited by 1,003
Cited by
Sorted by citations
Items 101–131 of 131
Gilbert, H.-Y., Li, Y., Yuki, K., Omura, K., Walter, M., Hanovice, N. J., Yin, Y., Huang, P. L., Danbolt, N. C., Liu, Z., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.07.652294 · Cited by 2
Protective mutations associated with APOE in Alzheimer’s disease
Ma, Y., Li, Y., Wu, G., Liu, L., Tian, M., Han, X., Chen, X., Xuan, X., Zheng, T., Gao, X., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03496-5 · Cited by 1
El-Ansary, A. K., Alabdali, A. N., Bacha, A. G. B., Alonazi, M. A., AL-Ayadhi, L. Y., & Bjørklund, G. (2026) · Scientific Reports · doi:10.1038/s41598-026-45737-1 · Cited by 2
Shuvaev, А. N., Belozor, О. S., Mozhei, O. I., Yakovleva, D. A., Shuvaev, А. N., Smolnikova, M. V., Пожиленкова, Е. А., Kasparov, S., Salmin, V. V., & Salmina, A. B. (2021) · Annals of Clinical and Experimental Neurology · doi:10.25692/acen.2021.1.6 · Cited by 1
Let's be Superficial about Ictal Activity
Dulla, C. G. (2017) · Epiliepsy currents/Epilepsy currents · doi:10.5698/1535-7597.17.5.299
Self-citationThresholding of sensory inputs by extrasynaptic glutamate receptors in olfactory bulb glomeruliPreprint
Gire, D. H., Zak, J. D., Bourne, J. N., Goodson, N., Lynch, B. E., Dulla, C. G., & Schoppa, N. E. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/341958
Self-citationGlutamate uptake and release at single adult corticostriatal synapses of normal and Huntington micePreprint
Dvorzhak, A., Helassa, N., Török, K., Schmitz, D., & Grantyn, R. (2018) · MDC Repository (Max-Delbrueck-Center for Molecular Medicine)
Pharmacological Ablation of Astroglia in a Rat Model of Parkinson’s Disease
Groulx, C. (2021) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2021-14407
Wolf, M. E. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733232114.793545840
Astrocytic Gi-GPCR activation enhances stimulus-evoked extracellular glutamatePreprint
Vaidyanathan, T. V., Tse, V., Lim, E., & Poskanzer, K. E. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.12.491656
Brymer, K. J., Hurley, E. P., Barron, J. C., Mukherjee, B., Barnes, J. R., Nafar, F., & Parsons, M. P. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.21.489062
Therapeutic targets and future directions
Jonak, C. R., Peterson, A. R., & Binder, D. K. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90099-7.00014-9
Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued in adulthoodPreprint
Venkatesan, S., Binko, M. A., Mielnik, C. A., Ramsey, A. J., & Lambe, E. K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.22.517556
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failurePreprint
Passlick, S., Ullah, G., & Henneberger, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.11.588988
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failurePreprint
Passlick, S., Ullah, G., & Henneberger, C. (2024) · eLife · doi:10.7554/elife.98834.1
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failurePreprint
Passlick, S., Ullah, G., & Henneberger, C. (2024) · eLife · doi:10.7554/elife.98834.2
McKenzie, S., Sommer, A. L., Donaldson, T. N., Pimentel, I., Kakani, M., Choi, I. J., Newman, E. L., & English, D. F. (2025) · eLife · doi:10.7554/elife.105183 · Cited by 5
Neuroglia's signaling: orchestrating neuronal gamma synchrony?
Andersen, M., Hirase, H., Kjærby, C., & Nedergaard, M. (2025) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001392
iGABASnFR Imaging Reveals Diffusion-Driven GABA Clearance in the Cerebral CortexPreprint
Gariepy, R. L., Blackman, J., Diamond, J. S., Dulla, C. G., & Armbruster, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.07.680664
Self-citationBrymer, K. J., Hurley, E. P., Barron, J. C., Mukherjee, B., Barnes, J. R., Nafar, F., & Parsons, M. P. (2024) · Figshare · doi:10.6084/m9.figshare.26568469
Kondrakhin, P. Y., & Kolpakov, F. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27010490
Biocapteurs implantables pour un monitorage intracérébral minimalement invasif
Chatard, C. (2018) · theses.fr (ABES) · doi:10.70675/1880b7a0z30d6z4a12za2b9za72ac2b0053b
The 3-Body Problem: How Astrocytes May Govern Plasticity
Watanabe, A., Guo, C., & Sjöström, P. J. (2026) · The Neuroscientist · doi:10.1177/10738584261445371
Rusleen, M. H. R., Mansor, N. I., Hamid, A. A., Nor, N. H. M., & Mohamed, Z. (2026) · Nutrients · doi:10.3390/nu18111819
Ratiometric iGluSnFr imaging to assess tonic glutamate in the cerebral cortexPreprint
Armbruster, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.12.731919
Self-citation
Metadata
- 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
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
