Exacerbation of epilepsy by astrocyte alkalization and gap junction uncoupling

Mariko Onodera, Jan Meyer, Kota Furukawa, Yuichi Hiraoka, Tomomi Aida, Kohichi Tanaka, Kenji F. Tanaka, Christine R. Rose, Ko Matsui

Research output: Contribution to journalArticlepeer-review

Abstract

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. K1 clearance relies on the K1 uptake by astrocytes and the subsequent diffusion of K1 through the astrocyte network. When astrocytes become uncoupled, K1 clearance becomes hindered. Accumulation of extracellular K1 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 K1 transients in response to glutamate became prolonged. Na1 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-E2GFP), we confirmed that astrocytes react to epileptiform activity with intracellular alkalization. Application of Na1/HCO3-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.

Original languageEnglish
Pages (from-to)2106-2118
Number of pages13
JournalJournal of Neuroscience
Volume41
Issue number10
DOIs
Publication statusPublished - 2021 Mar 10

Keywords

  • Astrocyte
  • Epilepsy
  • Gap junction
  • Na1/hco3-cotransporter
  • Ph
  • Potassium

ASJC Scopus subject areas

  • Neuroscience(all)

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