A novel rat model of Dravet syndrome recapitulates clinical hallmarks
A novel rat model of Dravet syndrome recapitulates clinical hallmarks
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DOI：
10.1016/j.nbd.2023.106193
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发表时间：
2023-06-15
影响因子：
6.1
通讯作者：
Wang, Hong
中科院分区：
文献类型：
--
作者：
Li, Miao;Yang, Lixin;Wang, Hong
Dravet综合征（DS）是一种使人衰弱的婴儿癫痫性脑病，其特征在于由高体温（高热）引起的癫痫发作、癫痫猝死（SUDEP）、认知障碍和行为障碍。DS最常见的原因是SCN 1A基因的单倍不足，该基因编码电压门控钠通道Nav1.1。在目前的DS小鼠模型中，癫痫表型严格依赖于遗传背景，大多数小鼠模型显示出比患者显著更高的SUDEP率。因此，我们寻求开发DS的替代动物模型。在这里，我们报告的生成和表征的Scn 1a halploinsufficiency大鼠模型的DS通过破坏Scn 1a等位基因。Scn 1a +/大鼠在大脑皮层、海马和丘脑中显示Scn 1a表达减少。纯合子无效大鼠过早死亡。杂合子动物对热诱导的癫痫发作高度敏感，这是DS的临床标志，但在没有癫痫发作诱导的情况下，存活、生长和行为正常。高血压诱导的癫痫发作激活Scn 1a +/-大鼠海马和下丘脑中不同的神经元组。Scn 1a +/-大鼠的脑电图（EEG）记录显示特征性发作EEG具有高振幅爆发，δ和θ功率显著增加。在初始高血压诱导的癫痫发作后，Scn 1a +/-大鼠自发发生非惊厥性和惊厥性癫痫发作。总之，我们建立了一个Scn 1a单倍不足大鼠模型，其表型与DS非常相似，为建立DS治疗方法提供了一个独特的平台。
Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, we report the generation and characterization of a Scn1a halploinsufficiency rat model of DS by disrupting the Scn1a allele. Scn1a+/rats show reduced Scn1a expression in the cerebral cortex, hippocampus and thalamus. Homozygous null rats die prematurely. Heterozygous animals are highly susceptible to heat-induced seizures, the clinical hallmark of DS, but are otherwise normal in survival, growth, and behavior without seizure induction. Hyperthermia-induced seizures activate distinct sets of neurons in the hippocampus and hypothalamus in Scn1a+/- rats. Electroencephalogram (EEG) recordings in Scn1a+/- rats reveal characteristic ictal EEG with high amplitude bursts with significantly increased delta and theta power. After the initial hyperthermia-induced seizures, non-convulsive, and convulsive seizures occur spontaneously in Scn1a+/- rats. In conclusion, we generate a Scn1a haploinsufficiency rat model with phenotypes closely resembling DS, providing a unique platform for establishing therapies for DS.