Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex
Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex
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DOI：
10.1093/hmg/ddr393
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Goto, June
中科院分区：
文献类型：
--
作者：
Anderl, Stefanie;Freeland, Megan;Goto, June
癫痫发作，特别是婴儿痉挛，常见于出生后不久患有结节性硬化症（TSC）的婴儿。人们担心，持续频繁的癫痫会对发育和认知产生长期影响。此外，TSC、皮质结节和巨细胞的标志性脑病理在孕晚期发育完全。这些观察结果使我们研究产前雷帕霉素在新的胎儿脑TSC模型中的益处。在这个Tsc1(cc) ne -cre（+）小鼠模型中，神经祖细胞中Tsc1的重组和缺失导致脑增大，mTOR过度激活，以及由于幼崽与母体相互作用减少而导致的P0新生儿死亡。产前给孕鼠单剂量雷帕霉素（1 mg/kg，皮下）可挽救突变小鼠的致死率。这一剂量的产前雷帕霉素治疗减少了突变大脑中mTOR通路的过度激活，而没有引起明显的妊娠丢失。在产后第8天开始继续使用雷帕霉素，使这些小鼠的存活时间延长至平均12天，并完全抑制了过度活跃的mTOR。然而，经过雷帕霉素处理的突变体大脑变大，脑细胞数量增加，表现出明显的跑步和发育迟缓。这些观察结果证明了产前雷帕霉素在产前发作的TSC脑模型中的治疗益处和局限性。我们的数据也提示了这种方法对TSC婴儿和母亲的可能性和局限性。
Epileptic seizures, particularly infantile spasms, are often seen in infants with tuberous sclerosis complex (TSC) soon after birth. It is feared that there are long-term developmental and cognitive consequences from ongoing, frequent epilepsy. In addition, the hallmark brain pathology of TSC, cortical tubers and giant cells are fully developed at late gestational ages. These observations have led us to examine the benefit of prenatal rapamycin in a new fetal brain model of TSC. In this Tsc1(cc) Nes-cre(+) mouse model, recombination and loss of Tsc1 in neural progenitor cells leads to brain enlargement, hyperactivation of mTOR, and neonatal death on P0 due to reduced pup-maternal interaction. A single dose of prenatal rapamycin given to pregnant dams (1 mg/kg, subcutaneous) rescued the lethality of mutant mice. This one dose of prenatal rapamycin treatment reduced hyperactivation of the mTOR pathway in the mutant brain without causing apparent pregnancy loss. Continued postnatal rapamycin beginning at day 8 extended the survival of these mice to a median of 12 days with complete suppression of hyperactive mTOR. However, the rapamycin-treated mutants developed enlarged brains with an increased number of brain cells, displaying marked runting and developmental delay. These observations demonstrate the therapeutic benefit and limitations of prenatal rapamycin in a prenatal-onset brain model of TSC. Our data also suggest the possibility and limitations of this approach for TSC infants and mothers.