Understanding the role of sodium channels in epilepsy

描述（由申请人提供）： SCN 1A电压门控钠通道（VGSC）的突变导致越来越多的疾病，包括遗传性癫痫伴热性惊厥+（GEFS+）、Dravet综合征（DS，或婴儿严重肌阵挛性癫痫）和家族性偏瘫性偏头痛。为了更好地理解SCN 1A功能障碍导致癫痫的机制，我们产生了具有人类SCN 1A突变R1648 H的转基因和敲入小鼠。这些突变体表现出自发性癫痫发作、癫痫发作阈值降低和寿命缩短。皮层神经元的电生理学分析显示兴奋性和抑制性神经元的功能均降低，但生物物理机制不同-兴奋性神经元的快速失活的负移电压依赖性与抑制性神经元的失活恢复缓慢。我们的研究结果和其他研究组的数据表明，GABA能抑制减少在GEFS+和DS的发病机制中起主要作用。然而，尚未确定中间神经元或锥体细胞中的SCN 1A功能与癫痫发作发生之间的直接因果关系。在目标1中，我们将选择性地删除中间神经元或锥体细胞中的Scn 1a，以直接建立每种细胞类型对癫痫发作的相对贡献。在目标2中，我们将检验以下假设：早期热性惊厥（FS）是GEFS+和DS的突出临床特征，对疾病进展有影响。我们还将探讨FS和疾病结局之间关系的机制基础以及可能的药物干预。与我们找到更好的癫痫治疗方法的最终目标进一步相关的是，我们观察到Scn 8a VGSC的功能改变可以恢复正常的癫痫发作阈值和DS Scn 1a敲除模型的寿命。这一观察结果使我们假设选择性靶向SCN 8A可能是DS的有效治疗方法，DS通常对现有药物难以治疗。在目标3中，我们将研究改变Scn 8a功能是否也可以改善其他遗传形式的癫痫和癫痫发作类型。这项研究将提供重要的信息，VGSCs在维持正常的神经元兴奋性和癫痫的发展中的作用。这些实验是创新的，临床相关的，并将刺激急需的转化研究。 公共卫生相关性： 大约40%的癫痫患者无法充分控制癫痫发作，更好地了解导致癫痫发作的机制将有助于开发更有效的治疗方法。在这项研究中，我们将研究的贡献，电压门控钠通道基因，SCN 1A和SCN 8A，癫痫发作的产生和癫痫发作的保护，分别。这项研究将提供有关癫痫机制的重要临床相关信息，以及通过选择性靶向SCN 8A可能治疗的不同癫痫亚型的范围。)

DESCRIPTION (provided by applicant): PROJECT SUMMARY Mutations in the SCN1A voltage-gated sodium channel (VGSC) are responsible for a growing number of disorders, including genetic epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (DS, or severe myoclonic epilepsy of infancy), and familial hemiplegic migraine. To better understand the mechanism by which SCN1A dysfunction leads to epilepsy, we generated transgenic and knock-in mice with the human SCN1A mutation R1648H. These mutants exhibit spontaneous seizures, reduced seizure thresholds, and shortened life spans. Electrophysiological analysis of cortical neurons revealed reduced function in both excitatory and inhibitory neurons, but the biophysical mechanisms were different - negatively shifted voltage dependence of fast inactivation in excitatory neurons versus slowed recovery from inactivation in inhibitory neurons. Our results and data from other groups led to the hypothesis that reduced GABAergic inhibition plays the major role in the pathogenesis of GEFS+ and DS. However, a direct causal link between SCN1A function in interneurons or pyramidal cells and seizure generation has not yet been established. In Aim 1, we will selectively delete Scn1a from either interneurons or pyramidal cells to directly establish the relative contribution of each cell type to seizure generation. In Aim 2, we will test the hypothesis that early-life febrile seizures (FSs), which are a prominent clinical feature of both GEFS+ and DS, have an impact on disease progression. We will also explore the mechanistic basis for the relationship between FSs and disease outcome and possible pharmacological interventions. Of further relevance to our ultimate goal of finding better treatments for epilepsy is our observation that altered function of the Scn8a VGSC can restore normal seizure thresholds and life spans to an Scn1a knockout model of DS. This observation led us to hypothesize that selective targeting of SCN8A may make an effective treatment for DS, which is often refractory to available medications. In Aim 3 we will investigate whether altering Scn8a function can also ameliorate other genetic forms of epilepsy and types of seizures. This study will provide important information on the role of VGSCs in the maintenance of normal neuronal excitability and in the development of epilepsy. These experiments are innovative, clinically relevant, and will stimulate much-needed translational research. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Approximately 40% of patients with epilepsy do not achieve adequate seizure control and a better understanding of the mechanisms that lead to seizure generation will facilitate the development of more effective treatments. In this study we will examine the contribution of the voltage-gated sodium channel genes, SCN1A and SCN8A, to seizure generation and seizure protection, respectively. This study will provide important, clinically relevant information on the mechanisms of epilepsy and the range of different epilepsy subtypes that can be potentially treated by selectively targeting SCN8A. )