Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current.
Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current.
复制标题
Dravet 综合征的敲入模型揭示了钠电流的组成性和条件性降低。
DOI：
10.1152/jn.00135.2014
复制
发表时间：
2014
影响因子：
2.5
通讯作者：
O'Dowd,DianeK
中科院分区：
文献类型：
--
作者：
Schutte,RyanJ;Schutte,SoleilS;Algara,Jacqueline;Barragan,EdenV;Gilligan,Jeff;Staber,Cynthia;Savva,YiannisA;Smith,MartinA;Reenan,Robert;O'Dowd,DianeK
SCN 1A钠通道基因中的数百个突变赋予了广泛的癫痫疾病，需要有效的模型系统来研究细胞机制和识别潜在的治疗靶点。我们最近发现，携带K1270 TSCN 1A突变的果蝇基因敲入果蝇，已知该突变可引起一种遗传性癫痫伴热性惊厥加重（GEFS+），表现出热诱导的钠电流活性增加和癫痫发作表型。为了确定不同的SCN 1A突变是否会像在人类中一样在果蝇中引起不同的表型，本研究集中在一个携带突变的基因敲入系上，该突变会导致更严重的癫痫发作，称为Dravet综合征（DS）。将DSSCN 1A突变（S1231 R）引入果蝇的惊厥通道基因，结果果蝇表现出自发性和热诱导性癫痫发作，具有独特的特征，并且比GEFS+果蝇的发作温度低。成年DS果蝇脑中GABA能中间神经元的电生理学研究首次在体内模型系统中揭示，错义DS突变导致钠电流活性和重复放电的组成性和条件性降低。此外，喂食5-羟色胺前体5-HTP可抑制DS而非GEFS+果蝇中的热诱导癫痫发作。DS和GEFS+ GABA能中间神经元中钠电流的明显改变表明，钠电流的功能丧失和获得改变都能够导致重复放电和癫痫发作表型减少。5-HTP对热诱导癫痫发作的突变特异性作用表明5-羟色胺途径是DS的潜在治疗靶点。
Hundreds of mutations in theSCN1Asodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated thatDrosophilaknock-in flies carrying the K1270TSCN1Amutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether differentSCN1Amutations cause distinct phenotypes inDrosophilaas they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DSSCN1Amutation (S1231R) into theDrosophilasodium channel genepararesults in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.
登录
查看更多内容
影响因子：
30.8
作者：
Dierick, Herman A.;Greenspan, Ralph J.
通讯作者：
Greenspan, Ralph J.
影响因子：
4.4
作者：
Albano, C.;Cupello, A.;Favale, E.
通讯作者：
Favale, E.
DOI：
10.3791/248
发表时间：
2007-01-01
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Gu, Huaiyu;O'Dowd, Diane K
通讯作者：
O'Dowd, Diane K
影响因子：
2.6
作者：
P. Widdess;O. Devinsky
通讯作者：
O. Devinsky
钠通道突变与癫痫——Jasper 的癫痫基本机制
DOI：
--
发表时间：
2012
期刊：
影响因子：
--
作者：
J. Noebels;M. Avoli;M. Rogawski;R. Olsen;A. Delgado
通讯作者：
A. Delgado