Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic Potentiation
Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic Potentiation
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DOI：
10.1523/jneurosci.0723-07.2007
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发表时间：
2007-10-17
影响因子：
5.3
通讯作者：
McCarthy, Ken D.
中科院分区：
文献类型：
--
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
在神经元活动期间，细胞外钾浓度（[K+]（out））升高，如果不纠正，会导致神经元去极化、过度兴奋和癫痫发作。从细胞外间隙清除K+，称为K+空间缓冲，被认为是星形胶质细胞的重要功能。大量研究结果表明，星形胶质细胞对（[K+]（out））的维持是通过内向整流K（ir）4.1通道的K+摄取介导的。为了研究该通道在星形胶质细胞生理学和神经元兴奋性中的作用，我们通过人胶质细胞酸性蛋白启动子gfa 2产生了针对星形胶质细胞的K（ir）4.1的条件性敲除（cKO）。K（ir）4.1 cKO小鼠过早死亡，并表现出严重的共济失调和应激诱导的癫痫发作。电生理记录显示严重的去极化的被动星形胶质细胞和复杂的胶质细胞在Kir4.1 cKO海马切片。复杂的细胞去极化似乎是一个直接的后果K（IR）4.1去除，而被动的星形胶质细胞去极化似乎是从一个间接的发展过程。此外，我们观察到一个显着的损失复杂的胶质细胞，提示的作用K（IR）4.1星形胶质细胞的发展。K（ir）4.1 cKO被动星形胶质细胞显示K+和谷氨酸摄取明显受损。令人惊讶的是，CA1锥体神经元的膜和动作电位特性，以及在CA1辐射层的基础突触传递似乎不受影响，而自发神经元活动减少的v cKO。然而，高频刺激显示大大提高强直后增强和短时程增强K（IR）4.1 cKO海马。我们的研究结果暗示了胶质细胞K（ir）4.1通道亚基在突触强度的调节中的作用。
During neuronal activity, extracellular potassium concentration ([K+](out)) becomes elevated and, if uncorrected, causes neuronal depolarization, hyperexcitability, and seizures. Clearance of K+ from the extracellular space, termed K+ spatial buffering, is considered to be an important function of astrocytes. Results from a number of studies suggest that maintenance of ([K+](out)) out by astrocytes is mediated by K+ uptake through the inward-rectifying K(ir)4.1 channels. To study the role of this channel in astrocyte physiology and neuronal excitability, we generated a conditional knock-out (cKO) of K(ir)4.1 directed to astrocytes via the human glial fibrillary acidic protein promoter gfa2. K(ir)4.1 cKO mice die prematurely and display severe ataxia and stress- induced seizures. Electrophysiological recordings revealed severe depolarization of both passive astrocytes and complex glia in Kir4.1 cKO hippocampal slices. Complex cell depolarization appears to be a direct consequence of K(ir)4.1 removal, whereas passive astrocyte depolarization seems to arise from an indirect developmental process. Furthermore, we observed a significant loss of complex glia, suggestive of a role for K(ir)4.1 in astrocyte development. K(ir)4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission in the CA1 stratum radiatum appeared unaffected, whereas spontaneous neuronal activity was reduced in the v cKO. However, high-frequency stimulation revealed greatly elevated posttetanic potentiation and short-term potentiation in K(ir)4.1 cKO hippocampus. Our findings implicate a role for glial K(ir)4.1 channel subunit in the modulation of synaptic strength.