期刊
BIOLOGICAL PSYCHIATRY
卷 82, 期 3, 页码 224-232出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2017.01.009
关键词
Autism spectrum disorder; Epilepsy; Na(V)1.2; electrophysiology; SCN2A; Seizure
资金
- Simons Foundation [SFARI 362242]
- National Institutes of Health [F32NS095580, R01 MH110928]
BACKGROUND: Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel Na(V)1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect Na(V)1.2 function and neuronal excitability are unclear. METHODS: We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express Na(V)1.2. RESULTS: In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability. CONCLUSIONS: This functional characterization thus identifies SCN2A mutation and Na(V)1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据