PDF(Pubmed)
Abstract：
Epilepsy is one of the most common neurological diseases. Epileptic individuals are faced with seizures, which are largely caused by enhanced neuronal excitability and/or decreased neuronal inhibitory activity. SCN2A encodes a neuronal voltage-gated sodium channel, NaV1.2 that is primarily found in excitatory neurons throughout the brain. NaV1.2 is most concentrated within the principal neurons of the corticostriatal circuit, which includes pyramidal neurons in the medial prefrontal cortex and medium spiny neurons in the striatum. In the early stage of adult development, the NaV1.2 channel plays critical roles in generation and propagation of action potentials in these neurons. Gain of Function variants of SCN2A results in unprovoked seizures and epilepsy, while loss-of-function variants of SCN2A is a leading cause for autism spectrum disorder as well as intellectual disability. Previous studies have shown that full deletion of Scn2a gene in mice is lethal and partial disruption of Scn2a gene (less than 50%) leads to inhibition of neuronal excitability. A recent study from Dr. Yang\'s laboratory revealed an unexpected result from mice with severe NaV1.2 deficiency and they demonstrated that severe deletion of Scn2a gene (around 68% gene disruption) in NaV1.2 triggers neuronal hyperexcitability in adult mice. Their findings may explain the puzzling clinical observation that certain individuals with NaV1.2 deficiency still develop unprovoked seizure. With the knowledge that using sodium-channel blockers simply exacerbates the seizure, the need for understanding the intrinsic nature of the NaV1.2 channel provides an important research topic in the future.
摘要：
癫痫是最常见的神经系统疾病之一。癫痫患者面临癫痫发作，这主要是由增强的神经元兴奋性和/或降低的神经元抑制活性引起的。SCN2A编码神经元电压门控钠通道，NaV1.2主要存在于整个大脑的兴奋性神经元中。NaV1.2最集中在皮质纹状体回路的主要神经元内，其中包括内侧前额叶皮质的锥体神经元和纹状体的中刺神经元。在成人发育的早期阶段，NaV1.2通道在这些神经元中动作电位的产生和传播中起关键作用。SCN2A的功能变异导致无源性癫痫发作和癫痫，而SCN2A的功能丧失变异体是自闭症谱系障碍和智力障碍的主要原因。先前的研究表明，小鼠中Scn2a基因的完全缺失是致命的，而Scn2a基因的部分破坏（小于50％）会导致神经元兴奋性的抑制。Yang博士实验室最近的一项研究揭示了严重NaV1.2缺乏症小鼠的意外结果，他们证明了NaV1.2中Scn2a基因的严重缺失（约68％的基因破坏）会触发成年小鼠的神经元过度兴奋。他们的发现可以解释令人困惑的临床观察，即某些患有NaV1.2缺乏症的人仍然会出现无缘无故的癫痫发作。知道使用钠通道阻滞剂只会加剧癫痫发作，需要了解NaV1.2通道的内在性质提供了未来的重要研究课题。
