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.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 13 Apr 2021|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. Funding was provided by Canadian Institutes of Health Research (CIHR) Grants FDN-148423 (to N. Sonenberg), PJT-162412 to (A.K.), and MOP130328 (to M.A.). Support to R.S. was provided by Richard and Edith Strauss Postdoctoral Fellowships in Medicine. We thank the N. Sonen-berg laboratory members, specifically I. Harvey, A. Lafrance, A. Sylvestre, and E. Migon, for support with animals and resources. J.-C.L. is supported by CIHR Project Grant PJT-153311 and by the Canada Research Chair in Cellular and Molecular Neurophysiology (CRC-950-231066).
© 2021 National Academy of Sciences. All rights reserved.
- MRNA translation
ASJC Scopus subject areas