Lemaire Louisiane, Desroches Mathieu, Rodrigues Serafim, Campillo Fabien
MathNeuro team, Inria Branch at the University of Montpellier, Montpellier, 34090, France.
MCEN research group, BCAM - Basque Center for Applied Mathematics, Bilbao, Basque Country, 48009, Spain.
Sci Rep. 2025 Sep 24;15(1):32749. doi: 10.1038/s41598-025-17468-2.
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 Na1.1, 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.
德拉韦综合征是一种发育性癫痫性脑病，其特征为耐药性癫痫发作早发以及多种合并症。这种严重且复杂病症的大多数病例是由主要在快速放电抑制性神经元中表达的钠通道Na1.1的突变所致。莱尔等人（《神经科学前沿》第15卷，2021年）表明，这些突变之一改变了通道激活的电压依赖性，以及缓慢失活的电压依赖性和动力学。将这三种效应纳入一个计算模型后，他们预测激活改变对通道功能的影响最大，因为它导致放电频率降低最为严重。使用一个针对快速放电抑制性神经元动力学量身定制的基于电导的模型，我们更深入地研究缓慢失活。我们利用这个非常缓慢的过程与系统其他部分之间的时间尺度差异进行多时间尺度分析。我们发现，在长时间刺激下，突变通道中较低电压下缓慢失活的起始会促进去极化阻滞，这是除频率降低之外另一种可能的放电缺陷。突变通道中缓慢失活加速的动力学加速了这种转变。这表明，对于某些德拉韦综合征变体而言，缓慢失活改变可能促成了病理机制。
