Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants’ converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.

中文翻译：

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mTORopathies中癫痫发生的趋同和发散机制

雷帕霉素复合物1（mTORC1）的机械靶标的过度激活归因于PI3K-mTOR通路和GATOR1复合物上的基因突变，导致一系列与皮层发育和顽固性癫痫病畸形相关的神经发育障碍（称为mTORopathies）。尽管这些基因变体对mTORC1活性的影响趋同，但新发现表明这些变体通过mTORC1依赖性和非依赖性机制促进癫痫发作。在这里，我们回顾了基于子宫电穿孔的mTORopathies动物模型的文献，该模型概括了mTORC1多动症的大脑镶嵌模式，并比较了不同的PI3K-mTOR途径和GATOR1复杂基因变异对皮层发育和癫痫的影响。我们报告了皮质锥体神经元放置的结果，形态学和电生理表型，并讨论造成这些变化及其对癫痫发生的作用的一些趋同和发散机制。除了雷帕霉素或依维莫司的mTORC1抑制作用以外，我们还讨论了癫痫的潜在治疗策略，这些策略可提供基于基因变异的个性化药物。