Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

结节性硬化症 (TSC) 是一种由TSC1或TSC2突变引起的神经发育障碍基因，编码负向调节 mTOR 复合物 1 (mTORC1) 信号传导的蛋白质。目前的治疗策略集中于用雷帕霉素及其衍生物抑制 mTOR。虽然雷帕霉素可有效改善 TSC 的某些方面，但慢性雷帕霉素会抑制 mTORC1 和 mTORC2，并与全身副作用相关。目前尚不清楚哪种 mTOR 复合物与 TSC 相关的大脑表型最相关。在这里，我们使用遗传策略选择性降低 TSC 小鼠模型中神经元 mTORC1 或 mTORC2 的活性。我们发现，mTORC1 成分 Raptor 的减少，而不是 mTORC2 成分 Rictor 的减少，重新平衡了 Tsc1 敲除神经元中的 mTOR 信号传导。Raptor 减少足以改善多种 TSC 相关表型，包括神经元肥大、大头畸形、髓鞘形成受损、网络过度活跃、和过早死亡。Raptor 下调代表了针对 TSC 神经系统表现的一种有前景的潜在治疗干预措施。