Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8.
Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8.
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DOI：
10.1111/gbb.12461
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Skelton MR
中科院分区：
文献类型：
--
作者：
Udobi KC;Kokenge AN;Hautman ER;Ullio G;Coene J;Williams MT;Vorhees CV;Mabondzo A;Skelton MR
肌酸转运蛋白（CrT; SLC 6A 8）缺乏症（CTD）是一种X连锁疾病，其特征在于严重的认知缺陷、语言障碍和脑肌酸（Cr）缺乏。在先前的研究中，我们产生了floxed Slc 6a 8（Slc 6a 8 flox）小鼠，以创建普遍存在的Slc 6a 8敲除（Slc 6a 8 −/y）小鼠。Slc 6a 8 −/y小鼠缺乏全身Cr，表现出认知缺陷。虽然Slc 6a 8 −/y小鼠与CTD患者具有相似的生化表型，但它们也显示出尺寸减小和游泳速度降低，这可能导致了观察到的缺陷。为了解决这个问题，我们通过将Slc 6a 8 flox小鼠与Nestin-cre小鼠杂交来创建脑特异性Slc 6a 8敲除（bKO）小鼠。bKO小鼠的脑Cr水平降低，同时维持外周组织中的正常Cr水平。有趣的是，bKO小鼠中Cr合成前体胍基乙酸的脑浓度增加。bKO小鼠在Morris水迷宫中具有更长的潜伏期和路径长度，而游泳速度没有降低。根据来自Slc 6a 8 −/y小鼠的数据，bKO小鼠在新物体识别以及上下文和线索恐惧条件反射方面表现出缺陷。与Slc 6a 8 −/y小鼠的数据相反，bKO小鼠也是过度活跃的。结果表明，大脑Cr的损失是普遍存在的Slc 6a 8 −/y小鼠中观察到的学习和记忆缺陷的原因。
Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8flox) mice to create ubiquitous Slc6a8 knock out (Slc6a8−/y) mice. Slc6a8−/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8−/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8−/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8−/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8−/y mice.
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