Departamento de Fisiologia Medica y Biofísica, Universidad de Sevilla, Av. Sanchez-Pizjuan 4, E- 41009 Sevilla, Spain.
CNS Neurol Disord Drug Targets. 2014 Feb;13(1):34-40. doi: 10.2174/18715273113126660184.
An increasing amount of evidence suggests that the dysregulation of the Akt-mTOR (Akt-mammalian Target Of Rapamycin) signaling network is associated with intellectual disabilities, such as fragile X, tuberous sclerosis and Rett's syndrome. The Akt-mTOR pathway is involved in dendrite morphogenesis and synaptic plasticity, and it has been shown to modulate both glutamatergic and GABAergic synaptic transmission. We have recently shown that the AktmTOR pathway is hyperactive in the hippocampus of Ts1Cje mice, a model of Down's syndrome, leading to increased local dendritic translation that could interfere with synaptic plasticity. Rapamycin and rapalogs are specific inhibitors of mTOR, and some of these inhibitors are Food and Drug Administration-approved drugs. In this review, we discuss the molecular basis and consequences of Akt-mTOR hyperactivation in Down's syndrome, paying close attention to alterations in the molecular mechanisms underlying synaptic plasticity. We also analyze the pros and cons of using rapamycin/rapalogs for the treatment of the cognitive impairments associated with this condition.
越来越多的证据表明，Akt-哺乳动物雷帕霉素靶蛋白（Akt-mTOR）信号网络的失调与智力障碍有关，如脆性 X 综合征、结节性硬化症和雷特综合征。Akt-mTOR 途径参与树突形态发生和突触可塑性，并且已经显示它可以调节谷氨酸能和 GABA 能突触传递。我们最近表明，在唐氏综合征模型 Ts1Cje 小鼠的海马体中 Akt-mTOR 途径过度活跃，导致局部树突翻译增加，这可能干扰突触可塑性。雷帕霉素和 rapalogs 是 mTOR 的特异性抑制剂，其中一些抑制剂是美国食品和药物管理局批准的药物。在这篇综述中，我们讨论了 Akt-mTOR 过度激活在唐氏综合征中的分子基础和后果，特别关注突触可塑性相关的分子机制的改变。我们还分析了使用雷帕霉素/rapalogs 治疗与这种情况相关的认知障碍的优缺点。
