eEF2/eEF2K Pathway in the Mature Dentate Gyrus Determines Neurogenesis Level and Cognition

Elham Taha, Sudarshan Patil, Iliana Barrera, Julia Panov, Mohammad Khamaisy, Christopher G. Proud, Clive R. Bramham, Kobi Rosenblum

Research output: Contribution to journalArticlepeer-review

Abstract

Levels of adult neurogenesis in the dentate gyrus (DG) of the hippocampus are correlated with unique cognitive functions. However, the molecular pathways controlling it are poorly understood. Here, we found that the known physiological ways to enhance neurogenesis converged on the eEF2/eEF2K pathway via AMPK in the DG. Enhancing the elongation phase of mRNA translation in eEF2K-knockout (eEF2K-KO) mice induced the expression of neurogenesis-related proteins in the hippocampus. We thus tested the hypothesis that inducing eEF2K-KO in mature neurons of the DG controls neurogenesis. Indeed, both general eEF2K-KO and targeted KO in DG excitatory mature neurons resulted in enhanced neurogenesis levels and upregulation of neurogenesis-related proteins. Increased neurogenesis was correlated with enhanced performance in DG-dependent learning. Moreover, general and local eEF2K-KO in old mice rejuvenated the DG, paving the way for better mechanistic understanding of how neurogenesis is controlled in the mature DG and possible treatments for incurable aging-associated diseases.

Original languageEnglish
Pages (from-to)3507-3521.e7
JournalCurrent Biology
Volume30
Issue number18
DOIs
StatePublished - 21 Sep 2020

Bibliographical note

Funding Information:
This research was supported by a grant from the Canadian Institutes of Health Research (CIHR) , the International Development Research Centre (IDRC) , the Israel Science Foundation (ISF) and the Azrieli Foundation ( ISF-IDRC 2395/2015 ); the ISF ISF 946/17 and ISF-UGC 2311/15 ; and TransNeuro ERANET JPND supported by the Israel Ministry of Health grant 3-14616 to K.R. E.T. was supported by the Israeli Planning and Budgeting Committee Program Fellowships , the Ministry of Science and Technology Program Fellowships , and Israel Society for Neuroscience for outstanding PhD students.

Funding Information:
This research was supported by a grant from the Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation (ISF-IDRC 2395/2015); the ISF ISF 946/17 and ISF-UGC 2311/15; and TransNeuro ERANET JPND supported by the Israel Ministry of Health grant 3-14616 to K.R. E.T. was supported by the Israeli Planning and Budgeting Committee Program Fellowships, the Ministry of Science and Technology Program Fellowships, and Israel Society for Neuroscience for outstanding PhD students. K.R. and E.T. initiated the project; K.R. supervised the research; K.R. and E.T. designed experiments; E.T. performed most of the research; S.P. and C.R.B. preformed the electrophysiological analysis; I.B. performed BrdU and DCX immunohistochemistry in eEF2K-KO mice; J.P. analyzed the steady-state deep proteomics experiment; M.K. performed context discrimination of fear conditioning in naive eEF2K floxed/floxed mice, genotyped, and maintained mice; C.G.P. generated the eEF2K floxed/floxed mice; and K.R. and E.T. wrote the manuscript with editing and input from all authors. We thank members of K.R.?s laboratory for suggestions and discussion, specifically Dr. Shunit Gal-Ben-Ari, Nathaniel Gould, and Gila Scherer for reading and editing the manuscript. We thank the veterinary team led by Dr. Barak Carmi at Haifa University for technical assistance and Dr. Alon Savidor from the de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center, and the Weizmann Institute of Science for conducting the proteomics experiment. The authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Agricultural and Biological Sciences (all)

Fingerprint

Dive into the research topics of 'eEF2/eEF2K Pathway in the Mature Dentate Gyrus Determines Neurogenesis Level and Cognition'. Together they form a unique fingerprint.

Cite this