Dysfunction of KCNK Potassium Channels Impairs Neuronal Migration in the Developing Mouse Cerebral Cortex
Dysfunction of KCNK Potassium Channels Impairs Neuronal Migration in the Developing Mouse Cerebral Cortex
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DOI：
10.1093/cercor/bhs387
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发表时间：
2014-04-01
期刊：
影响因子：
3.7
通讯作者：
Tagawa, Yoshiaki
中科院分区：
文献类型：
--
作者：
Bando, Yuki;Hirano, Tomoo;Tagawa, Yoshiaki
大脑皮层的发育部分依赖于神经活动，但可能有助于活动依赖性皮层发育的离子通道的身份尚不清楚。KCNK通道是成熟大脑皮层中神经元兴奋性的关键决定因素，KCNK家族的成员KCNK 9负责母体传播的精神发育迟滞综合征。在这里，我们研究了KCNK家族钾通道在皮质发育中的作用。通过使用子宫内电穿孔的RNAi敲除KCNK 2、9或10，损害了注定成为第II/III层神经元的晚出生皮层兴奋性神经元的迁移。通过共表达抗RNAi的功能性KCNK 9突变体来挽救KCNK 9敲低引起的迁移缺陷。此外，显性负突变体KCNK 9的表达，负责疾病，和电生理实验表明，离子通道功能参与迁移缺陷。钙成像显示，KCNK 9敲除或显性负突变KCNK 9的表达增加了显示钙瞬变的神经元的比例和自发钙瞬变的频率。KCNK 9敲低后出现的错位神经元停留在皮层深层，表现出延迟的形态成熟。综上所述，我们的研究结果表明，KCNK 9的功能障碍通过活性依赖性机制导致皮质中的迁移缺陷。
Development of the cerebral cortex depends partly on neural activity, but the identity of the ion channels that might contribute to the activity-dependent cortical development is unknown. KCNK channels are critical determinants of neuronal excitability in the mature cerebral cortex, and a member of the KCNK family, KCNK9, is responsible for a maternally transmitted mental retardation syndrome. Here, we have investigated the roles of KCNK family potassium channels in cortical development. Knockdown of KCNK2, 9, or 10 by RNAi using in utero electroporation impaired the migration of late-born cortical excitatory neurons destined to become Layer II/III neurons. The migration defect caused by KCNK9 knockdown was rescued by coexpression of RNAi-resistant functional KCNK9 mutant. Furthermore, expression of dominant-negative mutant KCNK9, responsible for the disease, and electrophysiological experiments demonstrated that ion channel function was involved in the migration defect. Calcium imaging revealed that KCNK9 knockdown or expression of dominant-negative mutant KCNK9 increased the fraction of neurons showing calcium transients and the frequency of spontaneous calcium transients. Mislocated neurons seen after KCNK9 knockdown stayed in the deep cortical layers, showing delayed morphological maturation. Taken together, our results suggest that dysfunction of KCNK9 causes a migration defect in the cortex via an activity-dependent mechanism.