Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, c/Cardenal Herrera Oria s/n, Santander 39011, Spain.
Neuroscience. 2012 Sep 18;220:158-68. doi: 10.1016/j.neuroscience.2012.06.031. Epub 2012 Jun 21.
The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. Partial display of DS phenotypes in mice harboring a single trisomy of Kcnj6 provides compelling evidence for a functional role of increased channel expression in some of the abnormal neurological phenotypes found in DS. Notably, the antiepileptic drug (AED) ethosuximide (ETH), but not other AEDs such as gabapentin (GAB), is known to inhibit KCNJ6 channels in mice. Here, we report the effect of chronic ETH and GAB on the behavioral and cognitive phenotypes of TS and disomic control (CO) mice. Neither drug significantly affected sensorimotor abilities, motor coordination or spontaneous activity in TS and CO mice. Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.
唐氏综合征（DS）的 Ts65Dn（TS）小鼠模型表现出该综合征的许多行为、神经形态学和神经化学表型。改变的 GABA 能传递似乎有助于解释 TS 小鼠认知障碍的机制。据报道，在 DS 和 TS 小鼠中，编码内向整流钾通道亚家族 J 成员 6（KCNJ6）的三体型基因的功能表达增加，随之而来的 GABA 能功能障碍。在携带 Kcnj6 单三体的小鼠中，DS 表型的部分表现提供了令人信服的证据，表明增加的通道表达在 DS 中发现的一些异常神经表型中具有功能作用。值得注意的是，抗癫痫药物（AED）乙琥胺（ETH），而不是其他 AED 如加巴喷丁（GAB），已知在小鼠中抑制 KCNJ6 通道。在这里，我们报告了慢性 ETH 和 GAB 对 TS 和二倍体对照（CO）小鼠行为和认知表型的影响。这两种药物都没有显著影响 TS 和 CO 小鼠的感觉运动能力、运动协调或自发活动。此外，ETH 和 GAB 没有在旷场或加迷宫测试中引起焦虑，没有改变 Morris 水迷宫中的表现，也没有影响提示或上下文恐惧条件反射。因此，我们的结果表明 KCNJ6 可能不是 DS 中的一个有前途的药物靶点候选物。作为推论，它们还表明，长期使用 ETH 和 GAB 没有不良的行为和认知影响。
