Exacerbation of Epilepsy by Astrocyte Alkalization and Gap Junction Uncoupling
Open accessAbstract
Seizures invite seizures. At the initial stage of epilepsy, seizures intensify with each episode; however, the mechanisms underlying this exacerbation remain to be solved. Astrocytes have a strong control over neuronal excitability and the mode of information processing. This control is accomplished by adjusting the levels of various ions in the extracellular space. The network of astrocytes connected via gap junctions allows a wider or more confined distribution of these ions depending on the open probability of the gap junctions. K + clearance relies on the K + uptake by astrocytes and the subsequent diffusion of K + through the astrocyte network. When astrocytes become uncoupled, K + clearance becomes hindered. Accumulation of extracellular K + leads to hyperexcitability of neurons. Here, using acute hippocampal slices from mice, we uncovered that brief periods of epileptiform activity result in gap junction uncoupling. In slices that experienced short-term epileptiform activity, extracellular K + transients in response to glutamate became prolonged. Na + imaging with a fluorescent indicator indicated that intercellular diffusion of small cations in the astrocytic syncytium via gap junctions became rapidly restricted after epileptiform activity. Using a transgenic mouse with astrocyte-specific expression of a pH sensor (Lck-E 2 GFP), we confirmed that astrocytes react to epileptiform activity with intracellular alkalization. Application of Na + /HCO 3 – cotransporter blocker led to the suppression of intracellular alkalization of astrocytes and to the prevention of astrocyte uncoupling and hyperactivity intensification both in vitro and in vivo . Therefore, the inhibition of astrocyte alkalization could become a promising therapeutic strategy for countering epilepsy development. SIGNIFICANCE STATEMENT We aimed to understand the mechanisms underlying the plastic change of forebrain circuits associated with the intensification of epilepsy. Here, we demonstrate that first-time exposure to only brief periods of epileptiform activity results in acute disturbance of the intercellular astrocyte network formed by gap junctions in hippocampal tissue slices from mice. Moreover, rapid clearance of K + from the extracellular space was impaired. Epileptiform activity activated inward Na + /HCO 3 – cotransport in astrocytes by cell depolarization, resulting in their alkalization. Our data suggest that alkaline pH shifts in astrocytes lead to gap junction uncoupling, hampering K + clearance, and thereby to exacerbation of epilepsy. Pharmacological intervention could become a promising new strategy to dampen neuronal hyperexcitability and epileptogenesis.
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Astrocytes and the vasculature may not only respond passively to neuronal activity but may also exhibit dynamics that precede changes in neuronal network states.
“Together, these findings suggest that astrocytes and the vasculature may not only respond passively to neuronal activity but may also exhibit dynamics that precede changes in neuronal network states39,53–55.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [54]
The Introduction and ‘Intracellular alkalization induces gap junction uncoupling’ section report that brief epileptiform activity changes astrocyte pH and coupling, which can impair potassium clearance and contribute to later neuronal hyperexcitability. This supports astrocyte dynamics preceding a subsequent change in neuronal activity, but the paper does not report corresponding dynamics of the vasculature. (LLM, conf=0.85)
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Self-citation
- Authors
- Onodera, M., Meyer, J., Furukawa, K., Hiraoka, Y., Aida, T., Tanaka, K., Tanaka, K. F., Rose, C. R., & Matsui, K.
- Affiliations
- Tohoku University (JP)
- Heinrich Heine University Düsseldorf (DE)
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Onodera, Mariko
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2021-01-21
- Volume
- 41
- Issue
- 10
- Pages
- 2106-2118
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC8018766
- OpenAlex
- W3094399095
- Cited by
- 50
- References
- 84
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 10 · 2023: 7 · 2022: 8 · 2021: 9
- FWCI
- 6.10
- 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)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- The Japan Neuroscience Society
- Funders
- Ministry of Education, Culture, Sports, Science, and Technology (16H01325, 18H04932, 18H05110, 19H03338, 18K19368)
- Japan Society for the Promotion of Science (19J12139)
- German Research Foundation (Ro2327/8-2)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- epilepsy, gap junction uncoupling, epileptiform activity, potassium clearance, Na+/HCO3- cotransporter, neuronal hyperexcitability, hippocampus, therapeutic target, sodium imaging
- MeSH terms
- Animals, Astrocytes, Epilepsy, Hippocampus, Hydrogen-Ion Concentration, Mice, Inbred BALB C, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Potassium, Gap Junctions, Mice
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