Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of the Ministry of Education of China, Guangzhou, China; Department of Neurology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, China.
Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Key Laboratory of Neurogenetics and Channelopathies of the Ministry of Education of China, Guangzhou, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt A):140-151. doi: 10.1016/j.pnpbp.2018.02.011. Epub 2018 Feb 23.
Kv1.1, a Shaker homologue potassium channel, plays a critical role in homeostatic regulation of neuronal excitability. Aberrations in the functional properties of Kv1.1 have been implicated in several neurological disorders featured by neuronal hyperexcitability. Fragile X syndrome (FXS), the most common form of inherited mental retardation, is characterized by hyperexcitability in neural network and intrinsic membrane properties. The Kv1.1 channel provides an intriguing mechanistic candidate for FXS. We investigated the development-related expression pattern of the Kv1.1 α-subunit by using a Fmr1 knockout (KO) mouse model of FXS. Markedly decreased protein expression of Kv1.1 was found in neonatal and adult stages when compared to age-matched wild-type (WT) mice. Immunohistochemical investigations supported the delayed development-related increases in Kv1.1 expression, especially in CA3 pyramidal neurons. By applying a Kv1.1-specific blocker, dendrotoxin-κ (DTX-κ), we isolated the Kv1.1-mediated currents in the CA3 pyramidal neurons. The isolated DTX-κ-sensitive current of neurons from KO mice exhibited decreased amplitude, lower threshold of activation, and faster recovery from inactivation. The equivalent reduction in potassium current in the WT neurons following application of the appropriate amount of DTX-κ reproduced the enhanced firing abilities of KO neurons, suggesting the Kv1.1 channel as a critical contributor to the hyperexcitability of KO neurons. The role of Kv1.1 in controlling neuronal discharges was further supported by the parallel developmental trajectories of Kv1.1 expression, current amplitude, and discharge impacts, with a significant correlation between the amplitude of Kv1.1-mediated currents and Kv1.1-blocking-induced firing enhancement. These data suggest that the expression of the Kv1.1 α-subunit has a profound pathological relevance to hyperexcitability in FXS, as well as implications for normal development, maintenance, and control of neuronal activities.
Kv1.1，一种 Shaker 同源钾通道，在神经元兴奋性的动态平衡调节中发挥关键作用。Kv1.1 功能特性的异常与几种以神经元过度兴奋为特征的神经紊乱有关。脆性 X 综合征 (FXS) 是最常见的遗传性智力障碍形式，其特征是神经网络和固有膜特性的过度兴奋。Kv1.1 通道为 FXS 提供了一个有趣的机械候选物。我们通过使用 FXS 的 Fmr1 敲除 (KO) 小鼠模型研究了 Kv1.1 α-亚基的发育相关表达模式。与年龄匹配的野生型 (WT) 小鼠相比，在新生儿和成年期发现 Kv1.1 蛋白表达明显减少。免疫组织化学研究支持 Kv1.1 表达的延迟发育相关增加，尤其是在 CA3 锥体神经元中。通过应用 Kv1.1 特异性阻断剂，树突毒素-κ (DTX-κ)，我们分离了 CA3 锥体神经元中的 Kv1.1 介导电流。来自 KO 小鼠的神经元中分离出的 DTX-κ 敏感电流幅度减小，激活阈值降低，失活后恢复更快。在应用适量 DTX-κ 后，WT 神经元中的钾电流等效减少，再现了 KO 神经元增强的放电能力，表明 Kv1.1 通道是 KO 神经元过度兴奋的关键贡献者。Kv1.1 在控制神经元放电中的作用进一步得到了 Kv1.1 表达、电流幅度和放电影响的平行发育轨迹的支持，Kv1.1 介导的电流幅度与 Kv1.1 阻断诱导的放电增强之间存在显著相关性。这些数据表明，Kv1.1 α-亚基的表达与 FXS 中的过度兴奋具有深远的病理相关性，并且对神经元活动的正常发育、维持和控制具有重要意义。
