Joshi Krutika, Shen Lily, Cao Feng, Dong Susan, Jia Zhengping, Cortez Miguel A, Snead O Carter
Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Canada; Neuroscience and Mental Health program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Canada.
Neuroscience and Mental Health program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Canada.
Epilepsy Res. 2018 Sep;145:82-88. doi: 10.1016/j.eplepsyres.2018.06.006. Epub 2018 Jun 12.
Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABAR agonist with a resultant recapitulation of the semiological, electrographic, and pharmacological phenotype of IS. One of the genes triplicated in Ts mice is the kcnj6 gene which codes for the G-protein inwardly rectifying potassium channel 2 (GIRK2) protein. We have shown that over expression of GIRK2 in Ts brain is necessary for the production of the GABAR agonist induced IS phenotype in the Ts mouse. Here, we ask the question whether the excess GIRK2 is sufficient for the production of the GABAR agonist induced IS phenotype.
To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice.
We now show that GABAR agonist-treated kcnj6 triploid mice failed to show susceptibility to the IS phenotype. Therefore, over expression of GIRK2 in the brain is necessary, but not sufficient to confer susceptibility to the GABAR agonist-induced IS phenotype in the Ts model of DS.
It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABAR agonist-induced IS phenotype.
婴儿痉挛症（IS）是一种灾难性的儿童癫痫性疾病，其特征为伸肌和/或屈肌痉挛、认知功能衰退以及特征性的脑电图异常。后者表现为棘波-慢波模式后跟随电极减量反应（EDR），即脑电图波形幅度变平。支撑IS的机制/神经回路尚不清楚。唐氏综合征（DS）患儿尤其易患IS。DS的标准小鼠模型是Ts65Dn突变小鼠（Ts）。利用Ts小鼠，我们建立了DS中IS的动物模型。该模型通过用GABAR激动剂处理Ts小鼠，从而重现了IS的症状学、电生理学和药理学表型。在Ts小鼠中三倍体化的基因之一是kcnj6基因，其编码G蛋白内向整流钾通道2（GIRK2）蛋白。我们已经表明，Ts脑内GIRK2的过表达对于在Ts小鼠中产生GABAR激动剂诱导的IS表型是必要的。在此，我们提出一个问题，即过量的GIRK2是否足以产生GABAR激动剂诱导的IS表型。
为了解决这个问题，我们使用了kcnj6三倍体小鼠，并通过视频分析比较痉挛次数，通过脑电图比较EDR事件与野生型小鼠的情况。
我们现在表明，用GABAR激动剂处理的kcnj6三倍体小鼠未表现出对IS表型的易感性。因此，脑内GIRK2的过表达是必要的，但不足以使DS的Ts模型对GABAR激动剂诱导的IS表型产生易感性。
因此，GIRK2可能与Ts脑中在产生GABAR激动剂诱导的IS表型时发生改变的另一种或多种因素协同起作用。
