Abstract
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.