The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3ca^H1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

雷帕霉素复合物 1 (mTORC1) 的机械/哺乳动物靶标整合了多种信号以调节关键的细胞过程，如 mRNA 翻译、脂质生物发生和自噬。mTOR 和 mTORC1 上游基因的种系和体细胞突变，如PTEN、TSC1/2、AKT3、PIK3CA和 GATOR1 和 KICSTOR 复合物的成分与各种癫痫症有关。在人类和动物模型中，mTORC1 活性的增加与癫痫的病理生理学有关，并且 mTORC1 抑制抑制了结节性硬化症人类和 mTORC1 活性升高的动物模型的癫痫发生。然而，mTORC1 依赖性翻译的作用和介导增强的 mTORC1 活性在癫痫发作中的作用的神经元细胞类型仍然未知。真核翻译起始因子 4E 结合蛋白 1 (4E-BP1) 和 2 (4E-BP2) 是 mTORC1 下游的翻译抑制因子。在这里，我们表明在小鼠中消融 4E-BP2 而不是 4E-BP1 会增加对戊四唑 (PTZ) 和红藻氨酸 (KA) 诱导的癫痫发作的敏感性。我们证明了 4E-BP2 在抑制中的缺失，但不是兴奋性神经元，导致对 PTZ 诱发的癫痫发作的易感性增加。此外，在小清蛋白中缺乏 4E-BP2 而非生长抑素或 VIP 抑制性神经元的小鼠表现出癫痫诱导阈值降低和小清蛋白神经元数量减少。包含人类的小鼠模型PIK3CA突变在小清蛋白神经元中选择性地增强 PI3K-AKT 通路 ( Pik3ca ^H1047R-Pvalb )的活性，显示出对 PTZ 诱导的癫痫发作的易感性。我们的数据将 4E-BP2 鉴定为癫痫发生的调节剂，并强调了增加 mTORC1 依赖性翻译在癫痫病理生理学中的小清蛋白神经元中的核心作用。