Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex
Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex
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DOI：
10.1016/j.neuropharm.2012.11.003
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发表时间：
2013-04-01
影响因子：
4.7
通讯作者：
Leocani, Letizia
中科院分区：
文献类型：
--
作者：
Cambiaghi, Marco;Cursi, Marco;Leocani, Letizia
结节性硬化症(TSC)是一种多系统遗传性疾病，由TSC1或TSC2基因突变导致mTOR通路过度激活引起，mTOR通路是突触可塑性的关键信号通路。TSC的特征是发生在不同器官的良性肿瘤和严重的神经精神症状，如癫痫、智力残疾、自闭症、焦虑和抑郁行为。雷帕霉素是一种有效的mTOR抑制剂，其治疗癫痫和神经症状的疗效尚不清楚。在胚胎端脑神经干细胞中TSC1缺失的小鼠模型中，我们通过高架迷宫(EPM)、开场试验(OFT)、强迫游泳试验(FST)和尾部悬挂试验(TST)分析了长期给予雷帕霉素后的焦虑和抑郁样行为。此外，还对背景脑电进行了频谱分析。EPM/OFT和FST分别显示，雷帕霉素处理的突变小鼠焦虑和抑郁样表型减少。这些结果与脑电功率谱结果一致。雷帕霉素在野生型小鼠身上也观察到了同样的效果。值得注意的是，在杂合子动物中，我们没有观察到雷帕霉素治疗后的任何脑电和/或行为变化。综上所述，这些结果表明，TSC1缺失和慢性雷帕霉素治疗可能在调节行为和大脑活动方面发挥作用，并指出背景EEG分析在跟踪大脑功能障碍与行为测试的同时具有潜在的用途。(C)2012爱思唯尔有限公司。保留所有权利。
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing. (c) 2012 Elsevier Ltd. All rights reserved.