Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis
Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis
复制标题
DOI：
10.1038/nm1788
复制
发表时间：
2008-08-01
期刊：
影响因子：
82.9
通讯作者：
Silva, Alcino J.
中科院分区：
文献类型：
--
作者：
Ehninger, Dan;Han, Sangyeul;Silva, Alcino J.
脑硬化症是一种由TSC 1（9 q34）或TSC 2（16p13.3）基因杂合突变引起的单基因疾病（1，2），通常与精神发育迟滞、自闭症和癫痫相关。即使患有结节性硬化症和正常智商（约50%）的个体（3-5）也通常受到特定神经心理问题的影响，包括长期记忆和工作记忆缺陷（6，7）。在这里，我们报告了Tsc 2基因中具有杂合失活突变的小鼠（Tsc 2（+/-）小鼠）（8）表现出学习和记忆缺陷。Tsc 2（+/-）小鼠的认知缺陷在没有神经病理学和癫痫发作的情况下出现，表明涉及其他疾病机制（5，9 -11）。我们发现，过度活跃的海马哺乳动物雷帕霉素靶（mTOR）信号导致海马CA 1区异常的长时程增强，从而导致海马依赖性学习的缺陷。这些缺陷包括在两个空间学习任务和上下文歧视的损害。值得注意的是，我们表明，在成年小鼠中使用mTOR抑制剂雷帕霉素的短暂治疗不仅挽救了突触可塑性，而且还挽救了结节性硬化症动物模型中的行为缺陷。本文提供的结果揭示了与结节性硬化症相关的一些认知缺陷的生物学基础，并且表明mTOR拮抗剂治疗可以改善该疾病小鼠模型的认知功能障碍。
Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene(1,2) and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%)(3-5) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits(6,7). Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice)(8) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved(5,9-11). We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.