Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation
Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation
复制标题
DOI：
10.1038/s41598-019-50627-w
复制
发表时间：
2019-10-02
影响因子：
4.6
通讯作者：
Hernandez-Alcoceba, Ruben
中科院分区：
文献类型：
--
作者：
Ricobaraza, Ana;Mora-Jimenez, Lucia;Hernandez-Alcoceba, Ruben
Dravet 综合征 (DS) 是一种伴有癫痫的脑病，伴有多种神经精神合并症。高达 90% 的病例是由 SCN1A 基因功能性单倍剂量不足引起的，该基因编码电压依赖性钠通道 (Nav1.1) 的 α 亚基。新靶向疗法的临床前开发需要可在遗传和临床水平上概括疾病的动物模型。在这里，我们描述了携带杂合的、临床相关的 SCN1A 突变 (A1783V) 的 C57BL/6 J 敲入小鼠品系，呈现出全谱的 DS 表现。这包括前 8 周龄期间 70% 的死亡率、热诱发癫痫发作的阈值降低（与对照同窝仔鼠相比降低 4.7 摄氏度）、认知障碍、运动障碍、焦虑、多动行为以及与环境相互作用的缺陷。相比之下，社交能力相对保留。电生理学研究显示自发性发作间期癫痫样放电，其以温度依赖性方式增加。癫痫发作是多灶性的，个体内部和个体之间的起源不同。它们表现出半球内/半球间传播，并经常导致全身强直阵挛发作。 F-18 标记的氟脱氧葡萄糖正电子发射断层扫描 (FDG-PET) 显示 Scn1a(WT/A1783V) 小鼠大脑中葡萄糖摄取量全面增加。我们得出的结论是，Scn1a(WT/A1783V) 模型是评估 DS 新疗法的强大研究平台。
Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 degrees C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. F-18-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1a(WT/A1783V) mice. We conclude that the Scn1a(WT/A1783V) model is a robust research platform for the evaluation of new therapies against DS.