Miyake Akira, Takahashi Shinji, Nakamura Yukihiro, Inamura Kohei, Matsumoto Shun-Ichiro, Mochizuki Shinobu, Katou Masao
Drug Discovery Research, Astellas Pharma Inc., Ibaraki 305-8585, Japan.
J Neurosci. 2009 Nov 18;29(46):14637-45. doi: 10.1523/JNEUROSCI.0901-09.2009.
The K+ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K+ channel genes are expressed in the CNS. The therapeutic potential of K+ channel blockers for cognitive enhancement has been discussed, but the contribution each K+ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K+ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K+ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K+ channel that contributes preferentially and bidirectionally to cognitive function.
钾离子通道是神经元兴奋性的决定因素之一，在基因上具有异质性，多种钾离子通道基因在中枢神经系统中表达。钾离子通道阻滞剂在认知增强方面的治疗潜力已被讨论，但每个钾离子通道基因对认知功能的贡献仍不清楚。BEC1（KCNH3）是钾离子通道超家族的成员，在前脑呈现优先分布。在此，我们展示了BEC1在认知功能中的关键作用。BEC1基因敲除小鼠在与工作记忆、参考记忆和注意力相关的行为任务中表现优于其野生型同窝小鼠。在杂合突变体中也观察到了性能增强。基因敲除小鼠既没有钾离子通道缺陷小鼠中常见的癫痫发作，也没有运动功能障碍。与基因敲除时相反，前脑BEC1的过表达导致这些任务的表现受损。还发现改变BEC1的表达可以改变海马神经元的兴奋性和突触可塑性。结果表明，BEC1可能是第一个对认知功能有优先和双向贡献的钾离子通道。
