Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington's disease
Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington's disease
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DOI：
10.1073/pnas.1405748112
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发表时间：
2015-02-17
影响因子：
11.1
通讯作者：
Faber, Donald S.
中科院分区：
文献类型：
--
作者：
Cao, Yumei;Bartolome-Martin, David;Faber, Donald S.
我们描述了小鼠背纹状体（纹状体输出神经元）中识别神经元的内在兴奋性的快速活动依赖稳态调节。它可以由短暂的活动爆发引起，以秒为时间尺度表示，限制重复射击，并可以将规则的射击模式转换为不规则的射击模式。我们发现这是由于产生M电流的KCNQ2/3通道的逐渐招募。在R6/2转基因亨廷顿氏病小鼠模型的纹状体输出神经元中，当神经元在体内过度活跃，小鼠开始表现出运动障碍时，这种稳态机制显著降低。此外，它可以通过瑞加滨（一种KCNQ通道激活剂）的灌注来恢复，慢性治疗可以改善运动性能。因此，m电流功能障碍可能导致这种神经退行性疾病的多动和网络失调特征，KCNQ2/3通道调节可能是治疗干预的靶点。
We describe a fast activity-dependent homeostatic regulation of intrinsic excitability of identified neurons in mouse dorsal striatum, the striatal output neurons. It can be induced by brief bursts of activity, is expressed on a time scale of seconds, limits repetitive firing, and can convert regular firing patterns to irregular ones. We show it is due to progressive recruitment of the KCNQ2/3 channels that generate the M current. This homeostatic mechanism is significantly reduced in striatal output neurons of the R6/2 transgenic mouse model of Huntington's disease, at an age when the neurons are hyperactive in vivo and the mice begin to exhibit locomotor impairment. Furthermore, it can be rescued by bath perfusion with retigabine, a KCNQ channel activator, and chronic treatment improves locomotor performance. Thus, M-current dysfunction may contribute to the hyperactivity and network dysregulation characteristic of this neurodegenerative disease, and KCNQ2/3 channel regulation may be a target for therapeutic intervention.