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

ABSTRACT: 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.

SUBMITTER: Patterson KC

PROVIDER: S-EPMC8665280 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Patterson Kelsey C KC Kahanovitch Uri U Gonçalves Christopher M CM Hablitz John J JJ Staruschenko Alexander A Mulkey Daniel K DK Olsen Michelle L ML

Glia 20200831 2

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 CO2/ H+ to regulate respiratory activity; however, mechanism(s) by which they do so remain unclear. Alterations in inward K+ currents represent a potential mecha ...[more]

PMID: 32865323

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Project description:BackgroundSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8+ T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8+ T cells in SLE remain to be identified.MethodsSingle-cell RNA sequencing (scRNA-seq) of PBMCs from a SLE family pedigree (including 3 HCs and 2 SLE patients) was performed to identify the SLE-associated CD8+ T cell subsets. Flow cytometry analysis of a SLE cohort (including 23 HCs and 33 SLE patients), qPCR analysis of another SLE cohort (including 30 HCs and 25 SLE patients) and public scRNA-seq datasets of autoimmune diseases were employed to validate the finding. Whole-exome sequencing (WES) of this SLE family pedigree was used to investigate the genetic basis in dysregulation of CD8+ T cell subsets identified in this study. Co-culture experiments were performed to analyze the activity of CD8+ T cells.FindingsWe elucidated the cellular heterogeneity of SLE and identified a new highly cytotoxic CD8+ T cell subset, CD161-CD8+ TEMRA cell subpopulation, which was remarkably increased in SLE patients. Meanwhile, we discovered a close correlation between mutation of DTHD1 and the abnormal accumulation of CD161-CD8+ TEMRA cells in SLE. DTHD1 interacted with MYD88 to suppress its activity in T cells and DTHD1 mutation promoted MYD88-dependent pathway and subsequently increased the proliferation and cytotoxicity of CD161-CD8+ TEMRA cells. Furthermore, the differentially expressed genes in CD161-CD8+ TEMRA cells displayed a strong out-of-sample prediction for case-control status of SLE.InterpretationThis study identified DTHD1-associated expansion of CD161-CD8+ TEMRA cell subpopulation is critical for SLE. Our study highlights genetic association and cellular heterogeneity of SLE pathogenesis and provides a mechanistical insight into the diagnosis and treatment of SLE.FundingsStated in the Acknowledgements section of the manuscript.

Dataset Information

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

Publications

K<sub>ir</sub> 5.1-dependent CO<sub>2</sub> /H<sup>+</sup> -sensitive currents contribute to astrocyte heterogeneity across brain regions.

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