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

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Kir 5.1-dependent CO2 /H+ -sensitive currents contribute to astrocyte heterogeneity across brain regions.
Glia ( IF 5.4 ) Pub Date : 2020-08-31 , DOI: 10.1002/glia.23898
Kelsey C Patterson ₁ , Uri Kahanovitch ₂ , Christopher M Gonçalves ₃ , John J Hablitz ₄ , Alexander Staruschenko _{5,

6} , Daniel K Mulkey ₃ , Michelle L Olsen ₂

Affiliation

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_ir4.1 and K_ir5.1 in the brainstem. Finally, the involvement of K_ir5.1 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.

中文翻译：

Kir 5.1 依赖性 CO2 /H+ 敏感电流导致脑区星形胶质细胞异质性。

星形胶质细胞异质性是一个新兴概念，其中脑区域内或之间的星形胶质细胞表现出可变的形态和/或基因表达谱，这可能反映了不同的功能作用。最近的证据表明，梯形后核（RTN）星形胶质细胞感知组织CO _2/ H ⁺的变化来调节呼吸活动；然而，它们这样做的机制仍不清楚。内向K ⁺电流的改变代表了CO ₂ /H ⁺信号可传递至神经元的潜在机制。在这里，我们在任一性别的大鼠中使用切片电生理学来表明，RTN 星形胶质细胞通过抑制内向整流钾 (K _ir ) 电导和膜去极化来对 CO _{2 /H + 做出内在反应，而皮质星形胶质细胞不表现出这种 CO 2} /H ⁺ ₂ /H ⁺敏感特性。 Ba ²⁺的应用模拟了 CO ₂ /H ⁺对 RTN 星形胶质细胞的影响，通过星形胶质细胞 K _ir样电流的减少和 RTN 神经元放电的增加来测量。这些CO ₂ /H ⁺敏感电流在发育过程中增加，同时脑干中K _ir 4.1 和K _ir 5.1 的表达也增加。最后，使用Kir5.1 KO大鼠验证了_Kir 5.1参与CO ₂ /H ⁺敏感电流。这些数据表明，CO ₂ /H ⁺抑制 K _ir可能控制星形胶质细胞通过细胞自主机制介导下游化学感受信号事件的程度。这些结果将 K _ir通道确定为发育早期潜在重要的区域 CO ₂ /H ⁺传感器，从而扩大了我们对星形胶质细胞异质性如何独特地支持特定神经回路和行为的理解。

更新日期：2020-08-31

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