ERG3钾通道介导的神经元内在兴奋性抑制和小鼠惊厥发作的预防。,The Journal of Physiology

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ERG3钾通道介导的神经元内在兴奋性抑制和小鼠惊厥发作的预防。
The Journal of Physiology ( IF 4.7 ) Pub Date : 2018-07-18 , DOI: 10.1113/jp275970
Kuo Xiao ₁ , Zhiming Sun ₁ , Xueqin Jin ₁ , Weining Ma ₂ , Yan Song ₁ , Shirong Lai ₁ , Qian Chen ₁ , Minghua Fan ₁ , Jingliang Zhang ₁ , Weihua Yue _{3,

4} , Zhuo Huang _{1,

5}

Affiliation

要点ERG3通道在中枢神经系统中具有高表达水平。敲低ERG3通道可增强海马CA1锥体神经元和齿状回颗粒细胞中神经元的内在兴奋性（这是由于快速超极化减少，动作电位产生的延迟时间缩短以及躯体兴奋性突触后突触电位的总和引起的）。在人类和小鼠海马癫痫灶中ERG3蛋白的表达降低。在海马中敲低ERG3通道可增强癫痫发作的敏感性，而用ERG通道激活剂NS-1643治疗的小鼠则较不容易发生癫痫。结果提供了有力的证据，证明ERG3通道在调节海马CA1锥体神经元和齿状回颗粒细胞的神经元内在兴奋性中起关键作用，并且在癫痫的发作和发展中起关键作用。摘要神经网络的输入输出关系在很大程度上取决于其神经元的内在特性。在各种生理和病理过程中，例如学习，记忆和癫痫病中，已经观察到内在特性的深刻变化。然而，内在兴奋性的获得性改变所基于的细胞和分子机制仍未被完全理解。这里，我们证明ERG3通道关键参与海马CA1锥体神经元和齿状回颗粒细胞内在兴奋性的调节。敲低ERG3通道可显着增加神经元内在的兴奋性，这主要是由于快速超极化后减少，动作电位产生的延迟时间缩短以及躯体兴奋性突触后突触电位的总和增加所致。有趣的是，在颞叶癫痫的人和小鼠脑组织中，ERG3蛋白的表达水平明显降低。此外，海马中ERG3通道的敲低显着增强了癫痫发作的敏感性，而用ERG通道激活剂NS-1643治疗的小鼠则不易发生癫痫发生。在一起我们的结果表明，ERG3通道在确定海马神经元的兴奋性中起重要作用，这些通道的失调可能与癫痫的发生有关。因此，ERG3通道可能是预防癫痫的新型治疗靶标。

"点击查看英文标题和摘要"

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice.

KEY POINTS ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy. ABSTRACT The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.

更新日期：2019-11-01

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