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

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. [Display omitted] •eEF2 pathway controls mature hippocampal neurogenesis•Enriched environment, physical exercise, and ketamine decrease peEF2 in the DG•eEF2K knockdown in DG excitatory neurons enhances neurogenesis•eEF2K knockdown in DG excitatory neurons enhances DG-dependent cognitive functions Taha et al. demonstrate that the eEF2 pathway controls mature hippocampal neurogenesis. Different neurogenic factors converge on the eEF2 pathway in the dentate gyrus to enhance neurogenesis. eEF2K knockdown in the dentate gyrus excitatory neurons enhances cognitive functions in young and old mice.