气候变化领域集成服务门户(CCPortal): 4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold

CCPortal

DOI	10.1073/pnas.2025522118
	4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold
	Sharma V.; Sood R.; Lou D.; Hung T.-Y.; Lévesque M.; Han Y.; Levett J.Y.; Wang P.; Murthy S.; Tansley S.; Wang S.; Siddiqui N.; Tahmasebi S.; Rosenblum K.; Avoli M.; Lacaille J.-C.; Sonenberg N.; Khoutorsky A.
发表日期	2021
ISSN	00278424
卷号	118 期号:15
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Epilepsy; MRNA translation; MTORC1
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179892
作者单位	Department of Biochemistry, McGill University, Montreal, QC H3A 2B4, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 2B4, Canada; Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada; Department of Anesthesia, Faculty of Dentistry, McGill University, Montreal, QC H3A 2B4, Canada; Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States; Sagol Department of Neurobiology, University of Haifa, Mount Carmel, Haifa, 3498838, Israel; Montreal Neurological Institute and Hospital, Department of Physiology, McGill University, Montreal, QC H3A 2B4, Canada; Department of Neurosciences, Centre for Interdisciplinary Research on Brain and Learning, Research Group on the Central Nervous System, Université de Montréal, Montréal, QC H3C 3J7, Canada
推荐引用方式 GB/T 7714	Sharma V.,Sood R.,Lou D.,et al. 4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold[J],2021,118(15).
APA	Sharma V..,Sood R..,Lou D..,Hung T.-Y..,Lévesque M..,...&Khoutorsky A..(2021).4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.Proceedings of the National Academy of Sciences of the United States of America,118(15).
MLA	Sharma V.,et al."4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold".Proceedings of the National Academy of Sciences of the United States of America 118.15(2021).