Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908-0710, USA.
J Neurophysiol. 2013 Sep;110(5):1144-57. doi: 10.1152/jn.00383.2013. Epub 2013 Jun 5.
During epileptogenesis a series of molecular and cellular events occur, culminating in an increase in neuronal excitability, leading to seizure initiation. The entorhinal cortex has been implicated in the generation of epileptic seizures in both humans and animal models of temporal lobe epilepsy. This hyperexcitability is due, in part, to proexcitatory changes in ion channel activity. Sodium channels play an important role in controlling neuronal excitability, and alterations in their activity could facilitate seizure initiation. We sought to investigate whether medial entorhinal cortex (mEC) layer II neurons become hyperexcitable and display proexcitatory behavior of Na channels during epileptogenesis. Experiments were conducted 7 days after electrical induction of status epilepticus (SE), a time point during the latent period of epileptogenesis and before the onset of seizures. mEC layer II stellate neurons from post-SE animals were hyperexcitable, eliciting action potentials at higher frequencies compared with control neurons. Na channel currents recorded from post-SE neurons revealed increases in Na current amplitudes, particularly persistent and resurgent currents, as well as depolarized shifts in inactivation parameters. Immunocytochemical studies revealed increases in voltage-gated Na (Nav) 1.6 isoform levels. The toxin 4,9-anhydro-tetrodotoxin, which has greater selectivity for Nav1.6 over other Na channel isoforms, suppressed neuronal hyperexcitability, reduced macroscopic Na currents, persistent and resurgent Na current densities, and abolished depolarized shifts in inactivation parameters in post-SE neurons. These studies support a potential role for Nav1.6 in facilitating the hyperexcitability of mEC layer II neurons during epileptogenesis.
在癫痫发生过程中，会发生一系列分子和细胞事件，最终导致神经元兴奋性增加，从而引发癫痫发作。在人类和颞叶癫痫动物模型中，内嗅皮层都与癫痫发作的产生有关。这种超兴奋性部分归因于离子通道活性的促兴奋性改变。钠通道在控制神经元兴奋性方面起着重要作用，其活性的改变可能促进癫痫发作的起始。我们试图研究在癫痫发生过程中，内侧内嗅皮层（mEC）II 层神经元是否变得过度兴奋，并表现出钠通道的促兴奋性行为。实验在电诱导癫痫持续状态（SE）后 7 天进行，此时处于癫痫发生的潜伏期，在癫痫发作开始之前。与对照神经元相比，来自 SE 后动物的 mEC 层 II 星形神经元兴奋性增加，可在更高频率下引发动作电位。从 SE 后神经元记录的钠通道电流显示钠电流幅度增加，特别是持久和再发性电流，以及失活参数的去极化偏移。免疫细胞化学研究显示电压门控钠（Nav）1.6 同工型水平增加。毒素 4,9-脱水四氢原小檗碱对 Nav1.6 比其他钠通道同工型具有更高的选择性，可抑制神经元过度兴奋，减少宏观钠电流、持久和再发性钠电流密度，并消除 SE 后神经元失活参数的去极化偏移。这些研究支持 Nav1.6 在促进癫痫发生过程中 mEC 层 II 神经元过度兴奋中的潜在作用。
