Abstract：
SCN1A gain-of-function variants are associated with early onset developmental and epileptic encephalopathies (DEEs) that possess distinct clinical features compared to Dravet syndrome caused by SCN1A loss-of-function. However, it is unclear how SCN1A gain-of-function may predispose to cortical hyper-excitability and seizures. Here, we first report the clinical features of a patient carrying a de novo SCN1A variant (T162I) associated with neonatal-onset DEE, and then characterize the biophysical properties of T162I and three other SCN1A variants associated with neonatal-onset DEE (I236V) and early infantile DEE (P1345S, R1636Q). In voltage clamp experiments, three variants (T162I, P1345S and R1636Q) exhibited changes in activation and inactivation properties that enhanced window current, consistent with gain-of-function. Dynamic action potential clamp experiments utilising model neurons incorporating Nav1.1. channels supported a gain-of-function mechanism for all four variants. Here, the T162I, I236V, P1345S, and R1636Q variants exhibited higher peak firing rates relative to wild type and the T162I and R1636Q variants produced a hyperpolarized threshold and reduced neuronal rheobase. To explore the impact of these variants upon cortical excitability, we used a spiking network model containing an excitatory pyramidal cell (PC) and parvalbumin positive (PV) interneuron population. SCN1A gain-of-function was modelled by enhancing the excitability of PV interneurons and then incorporating three simple forms of homeostatic plasticity that restored pyramidal cell firing rates. We found that homeostatic plasticity mechanisms exerted differential impact upon network function, with changes to PV-to-PC and PC-to-PC synaptic strength predisposing to network instability. Overall, our findings support a role for SCN1A gain-of-function and inhibitory interneuron hyperexcitability in early onset DEE. We propose a mechanism through which homeostatic plasticity pathways can predispose to pathological excitatory activity and contribute to phenotypic variability in SCN1A disorders.
摘要：
与由SCN1A功能丧失引起的Dravet综合征相比,SCN1A功能获得变异与具有不同临床特征的早发性发育性和癫痫性脑病(DEE)相关。然而,目前尚不清楚SCN1A功能获得是如何导致皮质过度兴奋和癫痫发作的.这里,我们首先报告了一名患者的临床特征，该患者携带与新生儿发病DEE相关的从头SCN1A变体（T162I），然后表征T162I和其他三个与新生儿发病或早期婴儿DEE相关的SCN1A变体的生物物理特性（I236V，P1345S,R1636Q)。在电压钳实验中,三个变体(T162I，P1345S和R1636Q）表现出增强窗口电流的激活和失活特性的变化，与函数增益一致。利用包含Nav1.1的模型神经元的动态动作电位钳制实验。通道支持所有四种变体的功能增益机制。这里,T162I,I236V,P1345S,和R1636Q变体相对于野生型表现出更高的峰值放电率，并且T162I和R1636Q变体产生超极化阈值和减少的神经元流变酶。为了探索这些变异对皮质兴奋性的影响，我们使用了包含兴奋性锥体细胞（PC）和小白蛋白阳性（PV）中间神经元群体的尖峰网络模型。通过增强PV中间神经元的兴奋性，然后结合三种简单形式的稳态可塑性来恢复锥体细胞放电率，从而对SCN1A功能获得进行了建模。我们发现稳态可塑性机制对网络功能产生了不同的影响，随着PV到PC和PC到PC突触强度的变化，会导致网络不稳定。总的来说,我们的发现支持SCN1A功能获得和抑制性中间神经元过度兴奋在早发性DEE中的作用.我们提出了一种机制，通过该机制，稳态可塑性途径可以使病理兴奋性活动易感，并有助于SCN1A疾病的表型变异性。
