An astrocytic basis of epilepsy
Open accessAbstract
Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown. Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting. In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity using tetrodotoxin (TTX) and voltage-gated Ca(2+) channel blockers. Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca(2+) in astrocytes. Two-photon imaging of live exposed cortex showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca(2+) signaling. Our results show an unanticipated key role for astrocytes in seizure activity. As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders.
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Glia are involved in a variety of neurological diseases, including schizophrenia, autism spectrum disorders, epilepsy, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke.
“Accumulating evidence has demonstrated that glia are involved in a variety of neurological diseases, including schizophrenia, autism spectrum disorders, epilepsy, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke (Matute et al., 2005;Tian et al., 2005;Nagai et al., 2007;Chen et al., 2009;Li et al., 2011;Lioy et al., 2011;Molofsky et al., 2012;Z”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Tian et al., 2005
Cites
Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo
Nimmerjahn, A., Kirchhoff, F., Kerr, J. N. D., & Helmchen, F. (2004) · Nature Methods · doi:10.1038/nmeth706 · Cited by 784 · see citing works
Beyond the role of glutamate as a neurotransmitter
Nedergaard, M., Takano, T., & Hansen, A. J. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn916 · Cited by 450 · see citing works
Self-citationCotrina, M. L., Lin, J. H.-C., López-Garcı́a, J. C., Naus, C. C. G., & Nedergaard, M. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-08-02835.2000 · Cited by 388 · see citing works
Self-citation
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Cited by
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Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
“…spectrum disorders, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke (Matute et al., 2005; Tian et al., 2005; Nagai et al., 2007; Chen et al., 2009; Li et al., 2011; Lioy et al., 2011; Molofsky et al., 2012; Zamanian et al., 2012).”
BackgroundSleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411 · see citing works
Self-citationAstrocytes: Biology and pathology
Sofroniew, M. V., & Vinters, H. V. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0619-8 · Cited by 5,196 · see citing works
Tripartite synapses: astrocytes process and control synaptic information
Perea, G., Navarrete, M., & Araque, A. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.05.001 · Cited by 1,820 · see citing works
Gliotransmitters Travel in Time and Space
Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H. R., Robitaille, R., & Volterra, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.007 · Cited by 1,308 · see citing works
Astrocyte reactivity and reactive astrogliosis: costs and benefits
Pekny, M., & Pekna, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00041.2013 · Cited by 934 · see citing works
Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury
Shlosberg, D., Benifla, M., Kaufer, D., & Friedman, A. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.74 · Cited by 897 · see citing works
The tripartite synapse: roles for gliotransmission in health and disease
Halassa, M. M., Fellin, T., & Haydon, P. G. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.12.005 · Cited by 852 · see citing works
Astrocytic complexity distinguishes the human brain
Oberheim, N. A., Wang, X., Goldman, S., & Nedergaard, M. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.08.004 · Cited by 739 · see citing works
Self-citationAstrocytic Ca2+ signaling evoked by sensory stimulation in vivo
Wang, X., Lou, N., Xu, Q., Tian, G.-F., Peng, W. G., Han, X., Kang, J., Takano, T., & Nedergaard, M. (2006) · Nature Neuroscience · doi:10.1038/nn1703 · Cited by 685 · see citing works
Self-citationRecessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2
Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M., Stephan, D. A., & Morton, D. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa052773 · Cited by 630 · see citing works
Activity-dependent structural and functional plasticity of astrocyte-neuron interactions
Theodosis, D. T., Poulain, D. A., & Oliet, S. H. R. (2008) · Physiological Reviews · doi:10.1152/physrev.00036.2007 · Cited by 531 · see citing works
Cortical spreading depression causes and coincides with tissue hypoxia
Takano, T., Tian, G.-F., Peng, W., Lou, N., Lovatt, D., Hansen, A. J., Kasischke, K. A., & Nedergaard, M. (2007) · Nature Neuroscience · doi:10.1038/nn1902 · Cited by 472 · see citing works
Self-citationDelekate, A., Füchtemeier, M., Schumacher, T., Ulbrich, C., Foddis, M., & Petzold, G. C. (2014) · Nature Communications · doi:10.1038/ncomms6422 · Cited by 332 · see citing works
Johannessen Landmark, C. (2008) · CNS Drugs · doi:10.2165/00023210-200822010-00003 · Cited by 316 · see citing works
Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine
Kjaerby, C., Andersen, M., Hauglund, N., Untiet, V., Dall, C., Sigurdsson, B., Ding, F., Feng, J., Li, Y., Weikop, P., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01102-9 · Cited by 306 · see citing works
Self-citationAstrocytes in the initiation and progression of epilepsy
Vezzani, A., Ravizza, T., Bedner, P., Aronica, E., Steinhäuser, C., & Boison, D. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00727-5 · Cited by 272 · see citing works
Emerging role for astroglial networks in information processing: from synapse to behavior
Pannasch, U., & Rouach, N. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.04.004 · Cited by 251 · see citing works
P2X Receptors in Health and Disease
Burnstock, G., & Kennedy, C. (2011) · Advances in Pharmacology · doi:10.1016/b978-0-12-385526-8.00011-4 · Cited by 213 · see citing works
Neuronal Transgene Expression in Dominant-Negative SNARE Mice
Fujita, T., Chen, M. J., Li, B., Smith, N. A., Peng, W., Sun, W., Toner, M. J., Kress, B. T., Wang, L., Benraiss, A., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2585-14.2014 · Cited by 141 · see citing works
Self-citationBonansco, C., & Fuenzalida, M. (2016) · Neural Plasticity · doi:10.1155/2016/8607038 · Cited by 138 · see citing works
Garcia, O., Torres, M., Helguera, P., Coskun, P., & Busciglio, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014200 · Cited by 122 · see citing works
Regulation of astrocyte glutamine synthetase in epilepsy
Eid, T., Tu, N., Lee, T.-S. W., & Lai, J. C. K. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.06.008 · Cited by 109 · see citing works
Astrocyte–neuron interplay in maladaptive plasticity.
Papa, M., De Luca, C., Petta, F., Alberghina, L., & Cirillo, G. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.010 · Cited by 104 · see citing works
Tuberous sclerosis: A primary pathology of astrocytes?
Sosunov, A. A., Wu, X., Weiner, H. L., Mikell, C. B., Goodman, R. R., Crino, P. D., & McKhann, G. M. (2008) · Epilepsia · doi:10.1111/j.1528-1167.2008.01493.x · Cited by 106 · see citing works
Mitochondrial calcium cycling in neuronal function and neurodegeneration
Walters, G. C., & Usachev, Y. M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1094356 · Cited by 105 · see citing works
Amiri, M., Hosseinmardi, N., Bahrami, F., & Janahmadi, M. (2013) · Journal of Computational Neuroscience · doi:10.1007/s10827-012-0432-6 · Cited by 99 · see citing works
Acute and Chronic Pain Processing in the Thalamocortical System of Humans and Animal Models
Groh, A., Krieger, P., Mease, R. A., & Henderson, L. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2017.09.042 · Cited by 101 · see citing works
Barros‐Barbosa, A. R., Fonseca, A. L., Guerra‐Gomes, S., Ferreirinha, F., Santos, A., Rangel, R., Lobo, M. G., Correia‐de‐Sá, P., & Cordeiro, J. M. (2016) · Epilepsia · doi:10.1111/epi.13263 · Cited by 48 · see citing works
Is there a role for vagus nerve stimulation therapy as a treatment of traumatic brain injury?
Kumaria, A., & Tolias, C. M. (2012) · British Journal of Neurosurgery · doi:10.3109/02688697.2012.663517 · Cited by 38 · see citing works
Tewari, S., & Parpura, V. (2013) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2013.00145 · Cited by 35 · see citing works
Properties of REM sleep alterations with epilepsy
Ikoma, Y., Takahashi, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac499 · Cited by 33 · see citing works
Local brain environment changes associated with epileptogenesis
Ikoma, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac355 · Cited by 26 · see citing works
Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy
Furukawa, K., Ikoma, Y., Niino, Y., Hiraoka, Y., Tanaka, K., Miyawaki, A., Hirrlinger, J., & Matsui, K. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70044 · Cited by 11 · see citing works
- Authors
- Tian, G.-F., Azmi, H., Takano, T., Xu, Q., Peng, W., Lin, J., Oberheim, N., Lou, N., Wang, X., Zielke, H. R., Kang, J., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- Rutgers New Jersey Medical School (US)
- New York Medical College (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Tian, Guo-Feng
- Venue
- Nature Medicine
- Published
- 2005-08-14
- Volume
- 11
- Issue
- 9
- Pages
- 973-981
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC1850946
- OpenAlex
- W2135328571
- Cited by
- 806
- References
- 3
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 29 · 2023: 20 · 2022: 21 · 2021: 25 · 2020: 24 · 2019: 32 · 2018: 31 · 2017: 26 · 2016: 37 · 2015: 39 · 2014: 61 · 2013: 47 · 2012: 76
- FWCI
- 33.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS38073, R01NS030007, NS39997, R01NS038073, NS 30007, R01NS039997)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD16596, P01HD016596)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- astrocytes, epilepsy, paroxysmal depolarization shift, calcium signaling, tetrodotoxin, antiepileptic drugs, valproic acid, gabapentin, phenytoin, seizure activity, astrocyte-targeted therapy
- MeSH terms
- Action Potentials, Animals, Anticonvulsants, Astrocytes, Epilepsy, Hippocampus, Photolysis, Rats, Sprague-Dawley, Glutamic Acid, Calcium Signaling, Rats
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