Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex.
Impaired astrocytic gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex.
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DOI：
10.1016/j.nbd.2009.01.010
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发表时间：
2009-05
影响因子：
6.1
通讯作者：
Wong M
中科院分区：
文献类型：
--
作者：
Xu L;Zeng LH;Wong M
星形胶质细胞的异常发生在结节性硬化症(TSC)患者的大脑中，可能与该病神经功能障碍的发病机制有关。在这里，我们报告了胶质细胞中TSC1基因失活的敲除小鼠(Tsc1GFAPCKO小鼠)表现出星形细胞连接蛋白Cx43的表达减少，以及与星形胶质细胞之间的缝隙连接偶联相关的损害。相应地，Tsc1GFAPCKO小鼠的海马片对刺激的反应增加了细胞外钾浓度。这种钾缓冲的损害可以归因于异常的缝隙连接偶联，因为缝隙连接抑制剂在对照中引起钾浓度的额外增加，而不是Tsc1GFAPCKO切片。此外，用哺乳动物靶标雷帕霉素抑制剂治疗可以逆转Cx43表达不足和钾缓冲受损的情况。这些结果表明，星形胶质细胞中TSC1的失活导致星形胶质细胞缝隙连接偶联和钾清除的缺陷，这可能是Tsc1GFAPCKO小鼠癫痫的原因之一。
Abnormalities in astrocytes occur in the brains of patients with Tuberous Sclerosis Complex (TSC) and may contribute to the pathogenesis of neurological dysfunction in this disease. Here, we report that knock-out mice with Tsc1 gene inactivation in glia (Tsc1GFAPCKO mice) exhibit decreased expression of the astrocytic connexin protein, Cx43, and an associated impairment in gap junction coupling between astrocytes. Correspondingly, hippocampal slices from Tsc1GFAPCKO mice have increased extracellular potassium concentration in response to stimulation. This impaired potassium buffering can be attributed to abnormal gap junction coupling, as a gap junction inhibitor elicits an additional increase in potassium concentration in control, but not Tsc1GFAPCKO slices. Furthermore, treatment with a mammalian target of rapamycin inhibitor reverses the deficient Cx43 expression and impaired potassium buffering. These findings suggest that Tsc1 inactivation in astrocytes causes defects in astrocytic gap junction coupling and potassium clearance, which may contribute to epilepsy in Tsc1GFAPCKO mice.
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影响因子：
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通讯作者：
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