The Impact of Aquaporin‐4 Deletion on K⁺‐Induced Astrocytic Swelling Depends on K⁺ Concentration

Astrocytes swell in response to elevations in extracellular K + concentration. This K + ‐induced swelling is widely believed to be due to astrocytic K + uptake, even if the underlying mechanisms are not fully understood. Conflicting results pertaining to the role of the brain water channel AQP4 in K + ‐induced swelling have been presented. This calls for revisiting the effect of AQP4 on K + ‐induced astrocytic swelling dynamics. In this study, we performed two‐photon microscopy of acute hippocampal slices from wildtype (WT) and Aqp4 −/− mice to assess astrocytic swelling in response to medium high 10 mM and pathologically high 50 mM [K + ] solutions. We demonstrate that K + ‐induced swelling is attenuated in Aqp4 −/− astrocytes exposed to 10 mM [K + ] o compared to WT. In slices exposed to 50 mM [K + ] o , peak swelling was similar between the two genotypes, whereas the cell volume recovery was more complete in Aqp4 −/− astrocytes. We demonstrate that the two [K + ] concentrations elicit fundamentally different astrocytic Ca 2+ signaling responses, and that the Ca 2+ signaling response differs between the genotypes in the 10 mM [K + ] o scenario. Our findings suggest that K + ‐induced astrocytic swelling has different mechanistic underpinnings, depending on the K + concentration to which the astrocytes are exposed, and that altered astrocytic Ca 2+ signaling is a putative mechanism involved.