Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.
Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.
复制标题
DOI：
10.1038/s42003-018-0099-2
复制
发表时间：
2018
影响因子：
5.9
通讯作者：
Yamakawa K
中科院分区：
文献类型：
--
作者：
Ogiwara I;Miyamoto H;Tatsukawa T;Yamagata T;Nakayama T;Atapour N;Miura E;Mazaki E;Ernst SJ;Cao D;Ohtani H;Itohara S;Yanagawa Y;Montal M;Yuzaki M;Inoue Y;Hensch TK;Noebels JL;Yamakawa K
编码电压门控钠通道Nav1.2的SCN2A基因突变与癫痫、智力残疾和自闭症有关。SCN2A功能获得突变导致早发性重度癫痫，而功能丧失突变导致轻度和/或晚发型癫痫的自闭症。在这里，我们显示了携带患者来源的无义突变的杂合子SCN2A基因敲除和敲入小鼠都表现出乙硫胺敏感的缺失样癫痫发作，与成年阶段的棘波放电相关。出乎意料的是，相同的癫痫发作在SCN2A杂合缺失的小鼠身上表现得更加明显，尤其是在背侧-端脑(例如，新皮质和海马区)兴奋神经元中，但在选择性缺失抑制神经元的小鼠中没有检测到。在成年野生型小鼠大脑皮质中，大部分Nav1.2表达在兴奋性神经元中，并且从近端(即轴突起始段)到远端轴突有稳定的增加和重新分布。这些结果表明，兴奋性神经元中的Nav1.2单倍体缺陷在SCN2A功能丧失突变患者的癫痫中起着关键作用。Ikuo Ogiwara等人。研究发现，电压门控钠通道Nav1.2，SCN2A编码基因的无义突变会导致小鼠失神样癫痫发作。他们还发现，兴奋性神经元中的Nav1.2单倍体缺陷，而不是抑制性神经元中的单倍体缺陷有助于癫痫的发生。
Mutations in the SCN2A gene encoding a voltage-gated sodium channel Nav1.2 are associated with epilepsies, intellectual disability, and autism. SCN2A gain-of-function mutations cause early-onset severe epilepsies, while loss-of-function mutations cause autism with milder and/or later-onset epilepsies. Here we show that both heterozygous Scn2a-knockout and knock-in mice harboring a patient-derived nonsense mutation exhibit ethosuximide-sensitive absence-like seizures associated with spike-and-wave discharges at adult stages. Unexpectedly, identical seizures are reproduced and even more prominent in mice with heterozygous Scn2a deletion specifically in dorsal-telencephalic (e.g., neocortical and hippocampal) excitatory neurons, but are undetected in mice with selective Scn2a deletion in inhibitory neurons. In adult cerebral cortex of wild-type mice, most Nav1.2 is expressed in excitatory neurons with a steady increase and redistribution from proximal (i.e., axon initial segments) to distal axons. These results indicate a pivotal role of Nav1.2 haplodeficiency in excitatory neurons in epilepsies of patients with SCN2A loss-of-function mutations. Ikuo Ogiwara et al. find that nonsense mutations in the gene coding for the voltage-gated sodium channel Nav1.2, SCN2A, cause absence-like seizures in mice. They also find that Nav1.2 haplodeficiency in excitatory, but not in inhibitory, neurons contributes to epileptogenesis.
登录
查看更多内容
影响因子：
16.2
作者：
Hevner, RF;Shi, LM;Rubenstein, JLR
通讯作者：
Rubenstein, JLR
影响因子：
25
作者：
Hoischen, Alexander;Krumm, Niklas;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
16.2
作者：
Buxbaum JD;Daly MJ;Devlin B;Lehner T;Roeder K;State MW;Autism Sequencing Consortium
通讯作者：
Autism Sequencing Consortium
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Carvill, Gemma L.;Heavin, Sinead B.;Yendle, Simone C.;McMahon, Jacinta M.;O'Roak, Brian J.;Cook, Joseph;Khan, Adiba;Dorschner, Michael O.;Weaver, Molly;Calvert, Sophie;Malone, Stephen;Wallace, Geoffrey;Stanley, Thorsten;Bye, Ann M. E.;Bleasel, Andrew;Howell, Katherine B.;Kivity, Sara;Mackay, Mark T.;Rodriguez-Casero, Victoria;Webster, Richard;Korczyn, Amos;Afawi, Zaid;Zelnick, Nathanel;Lerman-Sagie, Tally;Lev, Dorit;Moller, Rikke S.;Gill, Deepak;Andrade, Danielle M.;Freeman, Jeremy L.;Sadleir, Lynette G.;Shendure, Jay;Berkovic, Samuel F.;Scheffer, Ingrid E.;Mefford, Heather C.
通讯作者：
Mefford, Heather C.