Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits.
Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits.
复制标题
删除新生小鼠而非成年小鼠的肌酸转运蛋白基因会导致认知缺陷。
DOI：
10.1002/jimd.12137
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发表时间：
2019
影响因子：
4.2
通讯作者：
Skelton,MatthewR
中科院分区：
文献类型：
--
作者：
Udobi,KeneaC;Delcimmuto,Nicholas;Kokenge,AmandaN;Abdulla,ZuhairI;Perna,MarlaK;Skelton,MatthewR
肌酸（Cr）是一种胍基化合物，可为废三磷酸腺苷（ATP）的再生提供容易获得的磷酸盐库。脑铬缺乏导致中度至重度智力残疾、语言障碍和癫痫。Cr缺乏症最常见的原因是X连锁SLC 6A 8（肌酸转运蛋白; CrT）基因突变，称为CrT缺乏症（CTD）。需要解决的最关键领域之一是Cr是否是大脑发育所必需的。为了解决这个问题，使用由人泛素C（UBC）启动子驱动的他莫昔芬诱导型Cre重组酶，在新生（出生后第5天（P））或成年（P60）小鼠中敲除Slc 6a 8基因。在Slc 6a 8缺失后60天，在Morris水迷宫、新颖、物体识别和条件性恐惧中测试小鼠。此外，分析了过夜运动活性。在P5基因缺失的小鼠在Morris水迷宫和新物体识别方面表现出缺陷，而在P60基因敲除的小鼠中没有缺陷。有趣的是，P5基因敲除小鼠在黑暗阶段表现出活动过度;然而，当检查对照小鼠时，该效应是由于从P5至10给予他莫昔芬所致。两者合计，本研究的结果表明，铬是必要的，在涉及空间和对象学习的大脑发育期间。这项研究还强调了使用适当的控制组进行行为测试的持续重要性。
Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (ATP). The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X‐linkedSLC6A8(Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, theSlc6a8gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen‐inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5 to 10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.