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4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold [Neuroscience]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-04-13 , DOI: 10.1073/pnas.2025522118
Vijendra Sharma, Rapita Sood, Danning Lou, Tzu-Yu Hung, Maxime Lévesque, Yelin Han, Jeremy Y. Levett, Peng Wang, Shravan Murthy, Shannon Tansley, Siyan Wang, Nadeem Siddiqui, Soroush Tahmasebi, Kobi Rosenblum, Massimo Avoli, Jean-Claude Lacaille, Nahum Sonenberg, Arkady Khoutorsky

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 (Pik3caH1047R-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.



中文翻译:

小白蛋白神经元中4E-BP2依赖性翻译控制癫痫发作阈值[神经科学]

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,例如mRNA翻译,脂质生物发生和自噬。mTOR和mTORC1上游基因(例如PTENTSC1 / 2AKT3PIK3CA)中的种系和体细胞突变以及GATOR1和KICSTOR复合物的成分与各种癫痫病相关。在人类和动物模型中,增加的mTORC1活性都与癫痫的病理生理学相关,并且mTORC1抑制抑制了结节性硬化症患者和mTORC1活性升高的动物模型中的癫痫发生。然而,依赖mTORC1的翻译和介导癫痫发作中增强mTORC1活性的神经元细胞类型的作用仍然未知。真核翻译起始因子4E结合蛋白1(4E-BP1)和2(4E-BP2)是mTORC1下游的翻译阻遏物。在这里,我们显示消融4E-BP2而不是4E-BP1会增加小鼠对戊四氮(PTZ)和海藻酸(KA)诱发的癫痫发作的敏感性。我们证明了4E-BP2的缺失具有抑制作用,但不是兴奋性神经元引起对PTZ诱发的癫痫发作的敏感性增加。此外,小白蛋白中缺乏4E-BP2的小鼠,但生长抑素或VIP抑制神经元没有这种小鼠,其癫痫诱发阈值降低,小白蛋白神经元数量减少。藏有人类的老鼠模型在小白蛋白神经元中选择性增强PI3K-AKT途径(Pik3ca H1047R-Pvalb)活性的PIK3CA突变显示对PTZ诱发的癫痫发作易感。我们的数据确定4E-BP2作为癫痫发生的调节剂,并突出了在小白蛋白神经元中mTORC1依赖性翻译增加在癫痫的病理生理中的核心作用。

更新日期:2021-04-06
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