Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice.
Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice.
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DOI：
10.1038/nn.3691
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发表时间：
2014-05
影响因子：
25
通讯作者：
Khakh, Baljit S.
中科院分区：
文献类型：
--
作者：
Tong, Xiaoping;Ao, Yan;Faas, Guido C.;Nwaobi, Sinifunanya E.;Xu, Ji;Haustein, Martin D.;Anderson, Mark A.;Mody, Istvan;Olsen, Michelle L.;Sofroniew, Michael V.;Khakh, Baljit S.
亨廷顿病（HD）以纹状体中型棘神经元（MSN）功能障碍为特征，但其潜在机制尚不清楚。我们探讨了星形胶质细胞的作用，显示突变亨廷顿蛋白在HD患者和小鼠模型。我们发现R6/2和Q175 HD小鼠模型的症状发作与经典的星形胶质细胞增生无关，但与Kir4.1 K+通道功能表达降低相关，导致体内纹状体细胞外K+水平升高，从而增加MSN体外兴奋性。病毒传递Kir4.1通道纹状体星形胶质细胞恢复Kir4.1功能，正常化的细胞外K+，恢复MSN功能障碍方面，延长生存期和衰减R6/2小鼠的一些运动表型。这些发现表明，HD中MSN兴奋性改变的成分可能是由迄今为止未知的星形胶质细胞介导的K+稳态干扰引起的，揭示了星形胶质细胞和Kir4.1通道作为新的治疗靶点。
Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, which display mutant huntingtin in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models is not associated with classical astrogliosis, but is associated with decreased Kir4.1 K+ channel functional expression, leading to elevated in vivo levels of striatal extracellular K+, which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K+, recovered aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte–mediated K+ homeostasis, revealing astrocytes and Kir4.1 channels as novel therapeutic targets.
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影响因子：
5.3
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
通讯作者：
McCarthy, Ken D.
影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
影响因子：
3.6
作者：
Furutani, Kazuharu;Ohno, Yukihiro;Kurachi, Yoshihisa
通讯作者：
Kurachi, Yoshihisa
影响因子：
14.5
作者：
Behrens, P. F.;Franz, P.;Landwehrmeyer, G. B.
通讯作者：
Landwehrmeyer, G. B.
DOI：
10.1098/rspb.1967.0047
发表时间：
1967-01-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
KUFFLER, SW
通讯作者：
KUFFLER, SW