标题： 德拉维特综合征中通过缓慢的NaV1.1失活引起的去极化阻滞 显示英文标题

标题： Depolarization block induction via slow NaV1.1 inactivation in Dravet syndrome

摘要： 德拉维特综合征是一种发育性和癫痫性脑病，特征是早期出现的药物难治性癫痫发作和各种共患病。 这种严重且复杂的病理大多数病例是由于NaV1.1钠通道发生突变引起的，该通道主要表达在快速锋电位抑制性神经元中。 Layer等人（《前沿细胞神经科学》15, 2021）表明，这些突变中的一个会改变通道激活的电压依赖性，以及慢失活的电压依赖性和动力学。 将这三种效应纳入计算模型，他们预测改变的激活对通道功能影响最大，因为它导致了最严重的放电率降低。 使用一种针对快速锋电位抑制性神经元动态的基于导纳的模型，我们深入研究了慢失活。 我们利用这一非常缓慢的过程与系统其余部分之间的时间尺度差异来进行多时间尺度分析。 我们发现，在长时间刺激下，突变通道在较低电压下慢失活的起始促进了去极化阻断，这是除频率降低外另一种可能的放电缺陷。 突变通道中慢失活的加速动力学加快了这一转变。 这表明慢失活的改变可能对某些德拉维特变异类型有助于病理机制。 显示英文摘要

摘要： Dravet syndrome is a developmental and epileptic encephalopathy, characterized by the early onset of drug-resistant seizures and various comorbidities. Most cases of this severe and complex pathology are due to mutations of NaV1.1, a sodium channel mainly expressed in fast-spiking inhibitory neurons. Layer et al. (Front. Cell. Neurosci. 15, 2021) showed that one of these mutations alters the voltage dependence of channel activation, as well as the voltage dependence and kinetics of slow inactivation. Implementing the three effects into a computational model, they predict that altered activation has the largest impact on channel function, as it causes the most severe firing rate reduction. Using a conductance-based model tailored to the dynamics of fast-spiking inhibitory neurons, we look deeper into slow inactivation. We exploit the timescale difference between this very slow process and the rest of the system to conduct a multiple-timescale analysis. We find that, upon prolonged stimulation, the onset of slow inactivation at lower voltage in mutant channels promotes depolarization block, another possible firing deficit aside from frequency reduction. The accelerated kinetics of slow inactivation in mutant channels hastens this transition. This suggests that slow inactivation alterations might for some Dravet variant contribute to the pathological mechanism.