K_ir 5.1-dependent CO₂ /H⁺ -sensitive currents contribute to astrocyte heterogeneity across brain regions

Astrocyte heterogeneity is an emerging concept in which astrocytes within or between brain regions show variable morphological and/or gene expression profiles that presumably reflect different functional roles. Recent evidence indicates that retrotrapezoid nucleus (RTN) astrocytes sense changes in tissue CO_2/ H⁺ to regulate respiratory activity; however, mechanism(s) by which they do so remain unclear. Alterations in inward K⁺ currents represent a potential mechanism by which CO₂ /H⁺ signals may be conveyed to neurons. Here, we use slice electrophysiology in rats of either sex to show that RTN astrocytes intrinsically respond to CO₂ /H⁺ by inhibition of an inward rectifying potassium (K_ir ) conductance and depolarization of the membrane, while cortical astrocytes do not exhibit such CO₂ /H⁺ -sensitive properties. Application of Ba²⁺ mimics the effect of CO₂ /H⁺ on RTN astrocytes as measured by reductions in astrocyte K_ir -like currents and increased RTN neuronal firing. These CO₂ /H⁺ -sensitive currents increase developmentally, in parallel to an increased expression in K_ir 4.1 and K_ir 5.1 in the brainstem. Finally, the involvement of K_ir 5.1 in the CO₂ /H⁺ -sensitive current was verified using a Kir5.1 KO rat. These data suggest that K_ir inhibition by CO₂ /H⁺ may govern the degree to which astrocytes mediate downstream chemoreceptive signaling events through cell-autonomous mechanisms. These results identify K_ir channels as potentially important regional CO₂ /H⁺ sensors early in development, thus expanding our understanding of how astrocyte heterogeneity may uniquely support specific neural circuits and behaviors.