Astrocytic Swelling Due to Hypotonic or High K+ Medium Causes Inhibition of Glutamate and Aspartate Uptake and Increases Their Release

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Abstract
Astrocytic swelling occurs readily in ischemia and traumatic brain injury (TBI) as part of the cytotoxic or cellular edema response. Ischemia is known to produce large extracellular increases in both [K+] and excitatory amino acids (EAA) in vivo, and astrocytic swelling in vitro leads to marked release of EAA. In this study we compared the effect of swelling due to hypotonic media and high K+ medium on the uptake and release of EAA by rat primary astrocyte cultures in vitro. In both cases, there was a significant inhibition of uptake of [3H]l-glutamate and [3H]d-aspartate, and increased release of preloaded [3H]d-aspartate. The kinetics of the increased efflux was very different in response to hypotonic or high K+ media. In hypotonic medium there was a rapid initial release followed by a decline in the rate of release over time. This release was independent of whether Na+ was present. Upon exposure to high K+ medium there was a slow progressive increase in release of [3H]d-aspartate, which never showed any subsequent decline until the media was returned to normal [K+]. In high K+ media there was also an initial transient increase in [3H]d-aspartate release, which we attribute to reversal of the amino acid uptake system. The increased release due to hypotonic medium was not affected by a drop in temperature from 37 to 26°C, while the increased release due to high K+ medium was completely inhibited. The decreased uptake and increased release of EAA when astrocytes swell will short-circuit a presumed important, protective uptake system for EAA and may contribute to the increased levels of extracellular EAA seen during ischemia, TBI, and other pathologic states.