Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency.
Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency.
复制标题
DOI：
10.1371/journal.pone.0016187
复制
发表时间：
2011-01-13
期刊：
影响因子：
3.7
通讯作者：
Vorhees CV
中科院分区：
文献类型：
--
作者：
Skelton MR;Schaefer TL;Graham DL;Degrauw TJ;Clark JF;Williams MT;Vorhees CV
肌酸（Cr）转运蛋白（CrT; Slc 6a 8）基因突变导致脑Cr缺失和智力残疾、言语丧失和行为异常。到目前为止，还没有CrT缺乏症的小鼠模型来理解和开发这种疾病的治疗方法。本研究的目的是建立人CrT缺陷的小鼠模型。我们创建了Slc 6a 8的外显子2-4侧接loxP位点的小鼠，并将这些小鼠与Cre：CMV小鼠杂交以创建普遍存在的CrT敲除表达小鼠系。测试小鼠的学习和记忆缺陷，并测定Cr和神经递质水平。雄性CrT−/y（受影响）小鼠的大脑和肌肉中缺乏Cr，其他组织（包括心脏和睾丸）中的Cr显著减少。CrT−/y小鼠在Morris水迷宫中的获取和逆转学习过程中表现出路径长度增加。在探针试验期间，CrT−/y小鼠显示出与平台位置的平均距离增加。与CrT+/y相比，CrT−/y小鼠表现出减少的新物体识别和条件性恐惧记忆。CrT−/y小鼠的海马和前额皮质中的5-羟色胺和5-羟基吲哚乙酸增加。普遍存在的CrT基因敲除小鼠具有类似于人类CrT缺陷的学习和记忆缺陷，该模型应有助于理解这种疾病。
Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2–4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT−/y (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT−/y mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT−/y mice showed increased average distance from the platform site. CrT−/y mice showed reduced novel object recognition and conditioned fear memory compared to CrT+/y. CrT−/y mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.