Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility.
Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility.
复制标题
DOI：
10.1186/s40478-020-01082-6
复制
发表时间：
2020-11-30
影响因子：
7.1
通讯作者：
Hoshino M
中科院分区：
文献类型：
--
作者：
Hayase Y;Amano S;Hashizume K;Tominaga T;Miyamoto H;Kanno Y;Ueno-Inoue Y;Inoue T;Yamada M;Ogata S;Balan S;Hayashi K;Miura Y;Tokudome K;Ohno Y;Nishijo T;Momiyama T;Yanagawa Y;Takizawa A;Mashimo T;Serikawa T;Sekine A;Nakagawa E;Takeshita E;Yoshikawa T;Waga C;Inoue K;Goto YI;Nabeshima Y;Ihara N;Yamakawa K;Taya S;Hoshino M
Ihara癫痫大鼠(IER)是一种边缘样癫痫发作的突变模型，其病理和致病基因仍不清楚。在这份报告中，通过连锁分析，我们确定唐氏综合征细胞黏附分子样1(Dscaml1)是IER的负责基因。Dscaml1中的单碱基突变导致异常剪接，导致DSCAML1缺失。IERS增强了癫痫的易感性，加快了点燃建立。此外，这些动物的内嗅皮层(ECX)中的GABA能神经元严重减少。直接显示脑片兴奋状态的电压敏感染料成像显示IER ECX异常持久的兴奋性。这表明GABA能神经元的减少可能导致微弱的持续内嗅皮层激活，导致通过穿孔路径的自然点燃，从而可能导致齿状回肥大和癫痫发生。此外，我们在人类癫痫中发现了一个单核苷酸替换，它会导致DSCAML1(A2105T突变)中的一个氨基酸变化。突变的DSCAML1A2105T蛋白不存在于细胞表面，失去了其亲和性细胞黏附能力。我们建立了携带相应突变的敲入小鼠(Dscaml1A2105T)，观察到ECX中GABA能神经元减少以及棘波皮质图。我们认为DSCAML1是GABA能神经元定位于ECX和抑制啮齿动物癫痫敏感性所必需的。我们的发现表明，DSCAML1的突变可能会影响人类的癫痫易感性。本文的在线版本(10.1186/s40478-02020-6)包含向授权用户提供的补充材料。
The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1A2105T protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1A2105T) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans. The online version of this article (10.1186/s40478-020-01082-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
16.2
作者：
Fuerst, Peter G.;Bruce, Freyja;Tian, Miao;Wei, Wei;Elstrott, Justin;Feller, Maria B.;Erskine, Lynda;Singer, Joshua H.;Burgess, Robert W.
通讯作者：
Burgess, Robert W.
影响因子：
5.9
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
通讯作者：
Yamakawa K
DOI：
10.1006/bbrc.2001.5214
发表时间：
2001-07-20
影响因子：
3.1
作者：
Agarwala, KL;Ganesh, S;Yamakawa, K
通讯作者：
Yamakawa, K
影响因子：
5.3
作者：
Kajiwara, Riichi;Tominaga, Yoko;Tominaga, Takashi
通讯作者：
Tominaga, Takashi
影响因子：
2.5
作者：
Manly, KF;Cudmore, RH;Meer, JM
通讯作者：
Meer, JM