Clearance of activity-evoked K+ transients and associated glia cell swelling occur independently of AQP4: A study with an isoform-selective AQP4 inhibitor

Trine Lisberg Toft-Bertelsen, Brian Roland Larsen, Sofie Kjellerup Christensen, Himanshu Khandelia, Helle S. Waagepetersen, Nanna MacAulay*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

The mammalian brain consists of 80% water, which is continuously shifted between different compartments and cellular structures by mechanisms that are, to a large extent, unresolved. Aquaporin 4 (AQP4) is abundantly expressed in glia and ependymal cells of the mammalian brain and has been proposed to act as a gatekeeper for brain water dynamics, predominantly based on studies utilizing AQP4-deficient mice. However, these mice have a range of secondary effects due to the gene deletion. An efficient and selective AQP4 inhibitor has thus been sorely needed to validate the results obtained in the AQP4−/− mice to quantify the contribution of AQP4 to brain fluid dynamics. In AQP4-expressing Xenopus laevis oocytes monitored by a high-resolution volume recording system, we here demonstrate that the compound TGN-020 is such a selective AQP4 inhibitor. TGN-020 targets the tested species of AQP4 with an IC50 of ~3.5 μM, but displays no inhibitory effect on the other AQPs (AQP1-AQP9). With this tool, we employed rat hippocampal slices and ion-sensitive microelectrodes to determine the role of AQP4 in glia cell swelling following neuronal activity. TGN-020-mediated inhibition of AQP4 did not prevent stimulus-induced extracellular space shrinkage, nor did it slow clearance of the activity-evoked K+ transient. These data, obtained with a verified isoform-selective AQP4 inhibitor, indicate that AQP4 is not required for the astrocytic contribution to the K+ clearance or the associated extracellular space shrinkage.

Original languageEnglish
JournalGlia
Volume69
Issue number1
Pages (from-to)28-41
ISSN0894-1491
DOIs
Publication statusPublished - Jan 2021

Keywords

  • AQP4
  • glia cell swelling
  • inhibitor
  • TGN-020
  • [K] clearance

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