Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.
Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.
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DOI：
10.1038/ncomms2295
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
互惠社会互动障碍是自闭症谱系障碍的核心症状。遗传性疾病经常伴随自闭症谱系障碍，例如由TSC 1和TSC 2基因的单倍不足引起的结节性硬化症。越来越多的证据表明自闭症谱系障碍与信号转导之间的关系，涉及结节性硬化症复合体1，结节性硬化症复合体2和雷帕霉素的哺乳动物靶点。在这里，我们展示了与自闭症谱系障碍相关的行为异常，以及在结节性硬化症小鼠模型中通过雷帕霉素抑制剂雷帕霉素的哺乳动物靶点进行的恢复。在Tsc 2 +/−小鼠中，我们发现参与哺乳动物雷帕霉素靶信号传导的多个基因的转录增强，这依赖于激活的哺乳动物雷帕霉素靶信号传导，Akt的影响最小。这些发现表明哺乳动物雷帕霉素靶信号在结节性硬化症小鼠模型中缺乏社会行为中的关键作用，支持哺乳动物雷帕霉素靶抑制剂可用于与结节性硬化症综合征相关的自闭症谱系障碍的药理学治疗以及由雷帕霉素靶信号失调引起的其他病症。 脑硬化症是一种常染色体显性遗传的认知障碍，由影响TSC基因的突变引起。Sato及其同事研究了结节性硬化症复杂突变小鼠，发现即使在成年期，行为和解剖学异常也可以通过抑制雷帕霉素敏感的信号通路来逆转。
Impairment of reciprocal social interaction is a core symptom of autism spectrum disorder. Genetic disorders frequently accompany autism spectrum disorder, such as tuberous sclerosis complex caused by haploinsufficiency of the TSC1 and TSC2 genes. Accumulating evidence implicates a relationship between autism spectrum disorder and signal transduction that involves tuberous sclerosis complex 1, tuberous sclerosis complex 2 and mammalian target of rapamycin. Here we show behavioural abnormalities relevant to autism spectrum disorder and their recovery by the mammalian target of rapamycin inhibitor rapamycin in mouse models of tuberous sclerosis complex. In Tsc2+/− mice, we find enhanced transcription of multiple genes involved in mammalian target of rapamycin signalling, which is dependent on activated mammalian target of rapamycin signalling with a minimal influence of Akt. The findings indicate a crucial role of mammalian target of rapamycin signalling in deficient social behaviour in mouse models of tuberous sclerosis complex, supporting the notion that mammalian target of rapamycin inhibitors may be useful for the pharmacological treatment of autism spectrum disorder associated with tuberous sclerosis complex and other conditions that result from dysregulated mammalian target of rapamycin signalling. Tuberous sclerosis complex is an autosomal dominant cognitive disorder caused by mutations affecting TSC genes. Sato and colleagues examine tuberous sclerosis complex mutant mice and find that the behavioural and anatomical abnormalities can be reversed by inhibiting rapamycin-sensitive signalling pathways, even in adulthood.
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影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
通讯作者：
Franz, David Neal
影响因子：
6.4
作者：
de Vries, Petrus J.;Hunt, Ann;Bolton, Patrick F.
通讯作者：
Bolton, Patrick F.
影响因子：
30.8
作者：
KOBAYASHI, T;HIRAYAMA, Y;HINO, O
通讯作者：
HINO, O
影响因子：
14.5
作者：
Bolton, PF;Park, RJ;Pickles, A
通讯作者：
Pickles, A
DOI：
10.1073/pnas.151033798
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kobayashi, T;Minowa, O;Hino, O
通讯作者：
Hino, O