A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging
A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging
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DOI：
10.1093/hmg/ddw252
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发表时间：
2016-10-01
影响因子：
3.5
通讯作者：
Pizzorusso, Tommaso
中科院分区：
文献类型：
--
作者：
Baroncelli, Laura;Molinaro, Angelo;Pizzorusso, Tommaso
肌酸（Cr）转运蛋白（CrT）基因突变导致脑肌酸缺乏综合征-1（CCDS 1），这是一种X连锁代谢紊乱，其特征为脑Cr缺乏导致智力残疾、癫痫发作、运动和自闭症样行为障碍、语言和言语障碍。由于没有关于这种疾病的神经和分子基础的数据，我们在CCDS 1小鼠模型中对与CrT缺乏相关的行为和病理改变进行了纵向分析。我们发现了早熟的认知和类似自闭症的缺陷，模仿了人类CCDS 1的早期关键特征。此外，突变小鼠表现出短期和长期陈述性记忆的进行性损伤，表明大脑老化早期。病理学检查显示GABA能突触明显缺失，小胶质细胞明显活化，海马神经发生减少，自发荧光脂褐素积聚。我们的数据表明，脑铬耗竭导致早期智力残疾和晚期进行性认知下降，并确定新的目标，以设计干预策略，旨在克服脑CCDS 1的变化。
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autisticlike behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-termdeclarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.