Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel.
Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel.
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携带 szt1 突变的小鼠表现出癫痫易感性增加以及对作用于 m 通道的化合物的敏感性改变。
DOI：
10.1111/j.0013-9580.2004.65703.x
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发表时间：
2004
期刊：
影响因子：
5.6
通讯作者：
White,HSteve
中科院分区：
文献类型：
--
作者：
Otto,JamesF;Yang,Yan;Frankel,WayneN;Wilcox,KarenS;White,HSteve
目的：编码M型K+通道亚基（KCNQ 2/KCNQ 3）和烟碱乙酰胆碱受体（CHRNA 4）的基因突变导致人类癫痫。本研究的目的是检查Szt 1突变的影响，该突变不仅删除了小鼠Kcnq 2的大部分C末端，而且还使Chnra 4和Arfgap-1基因半合子，对癫痫发作的敏感性和对靶向M型K+channel.Methods的药物的敏感性：通过电惊厥阈值（ECT）测试在C57 BL/6 J-Szt 1/+（Szt 1）和同窝对照C57 BL/6 J +/+（B6）小鼠中评估M通道阻断剂利诺吡啶（LPD）的促惊厥作用和M通道增强剂瑞替加滨（RGB）的抗惊厥作用。TheSzt 1突变对最小阵挛，最小强直性后肢伸展，和部分精神性癫痫发作的影响进行了评估，通过不同的刺激强度和frequency.Results：Szt 1小鼠癫痫发作阈值显着降低，相对于B6同窝小鼠在最小阵挛，最小强直性后肢伸展，和部分精神性癫痫发作模型。给小鼠注射LPD和RGB，并进行ECT测试。在最小阵挛发作模型中，Szt 1小鼠对LPD的敏感性显著高于B6小鼠[中位有效剂量（ED_（50））分别为3.4 ± 1.1 mg/kg和7.6 ± 1.0 mg/kg];在部分精神病发作模型中，Szt 1小鼠对RGB的敏感性显著低于B6小鼠（ED 50分别为11.6 ± 1.4 mg/kg和3.4 ± 1.3 mg/kg）。
Purpose:Mutations in the genes that encode subunits of the M‐type K+channel (KCNQ2/KCNQ3) and nicotinic acetylcholine receptor (CHRNA4) cause epilepsy in humans. The purpose of this study was to examine the effects of theSzt1mutation, which not only deletes most of the C‐terminus of mouseKcnq2, but also renders theChnra4andArfgap‐1genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M‐type K+channel.Methods:The proconvulsant effects of the M‐channel blocker linopirdine (LPD) and anticonvulsant effects of the M‐channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J‐Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice. The effects of theSzt1mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency.Results:Szt1mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model,Szt1mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED50) = 3.4 ± 1.1 mg/kg and 7.6 ± 1.0 mg/kg, respectively]; in the partial psychomotor seizure model,Szt1mice were significantly less sensitive to RGB than were B6 mice (ED50= 11.6 ± 1.4 mg/kg and 3.4 ± 1.3 mg/kg, respectively).Conclusions:These results suggest that theSzt1mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model.