Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.
Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.
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DOI：
10.1371/journal.pone.0151148
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Baraban SC
中科院分区：
文献类型：
--
作者：
Grone BP;Marchese M;Hamling KR;Kumar MG;Krasniak CS;Sicca F;Santorelli FM;Patel M;Baraban SC
突触机制基因突触融合蛋白结合蛋白1（STXBP 1，也称为MUNC 18 -1）的突变与儿童癫痫和其他神经发育障碍有关。斑马鱼STXBP 1同源物（stxbp 1a和stxbp 1b）具有高度保守的序列，并且在斑马鱼幼虫脑中显著表达。为了了解stxbp 1a和stxbp 1b的功能，我们使用CRISPR/Cas9基因编辑产生了功能缺失突变，并研究了斑马鱼幼虫的脑电活动、行为、发育、心脏生理学、代谢和存活。与对照组相比，纯合子stxbp 1a突变体表现出严重的运动缺乏，脑电活动低，心率低，葡萄糖和线粒体代谢降低，早期死亡。另一方面，纯合子stxbp 1b突变体具有自发性电图癫痫发作，并且对运动诱导的“暗闪光”视觉刺激的自发活动反应降低，尽管表现出正常的代谢、心率、存活率和基线自发活动。我们在这些新产生的斑马鱼突变系中的发现表明，斑马鱼重演了与人类突触融合蛋白结合蛋白1突变相关的临床表型。
Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing “dark-flash” visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations.