Circadian activities of the brain MNK-eIF4E signalling axis contribute to diurnal rhythms of some cognitive functions

Dong Liu, Jin Li, Hao Lin, Ethan Lorsung, Nam Le, Rubal Singla, Abhishek Mishra, Rikiro Fukunaga, Ruifeng Cao

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Although it is well recognized that the circadian timing system profoundly influences cognitive performance, the underlying molecular mechanisms remain poorly defined. Our previous work has found that the mitogen-activated protein kinase-interacting kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis, a conserved cellular signalling pathway regulating mRNA translation, modulates the function of the suprachiasmatic nucleus (SCN), the master circadian clock. Here, with the use of a combination of genetic, biochemical and behavioural approaches, we investigated the distribution and temporal regulation of eIF4E phosphorylation in the brain and its role in regulating the diurnal oscillations of some aspects of cognition in mice. We found that activities of the MNK-eIF4E axis, as indicated by the level of eIF4E phosphorylation at Ser209, exhibited significant circadian oscillations in a variety of brain regions, including but not limited to the prefrontal cortex, the hippocampus, the amygdala and the cerebellum. Phosphorylated eIF4E was enriched in neurons but not in astrocytes or microglia. Mice lacking eIF4E phosphorylation (eIF4ES209A/S209A) or the MNKs (Mnk1−/−,2−/−), the kinases that phosphorylate eIF4E, exhibited impaired diurnal variations of novel object recognition, object location memory, Barnes maze learning and ambulatory activities. Together, these results suggest that circadian activities of the MNK-eIF4E axis contribute to the diurnal rhythms of some cognitive functions, highlighting a role for rhythmic translational control in circadian regulation of cognitive performance.

Original languageEnglish (US)
Pages (from-to)3553-3569
Number of pages17
JournalEuropean Journal of Neuroscience
Issue number1
StatePublished - Jul 2022

Bibliographical note

Funding Information:
We thank A. Khoutorsky for critical reading of the manuscript and N. Sonenberg for providing the mice. This study was supported by a grant from NIH (NS118026), a grant from the Winston and Maxine Wallin Neuroscience Discovery Fund, a grant from the University of Minnesota Foundation and a grant from Whiteside Institute for Clinical Research to R.C. eIF4E S209A/S209A

Publisher Copyright:
© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


  • MNK
  • behaviour
  • circadian rhythm
  • cognition
  • eIF4E
  • mouse
  • phosphorylation


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