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 Ca²⁺ signaling responses, and that the Ca²⁺ 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 Ca²⁺ signaling is a putative mechanism involved.