In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice

Summary Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases.
Highlights • Expression of 4 Yamanaka factors (YFs) achieved in vivo by cyclic induction in brain • H3K9 trimethylation is prevented by cyclic induction of the YFs • YFs elevated levels of migrating cells containing neurogenic markers doublecortin and calretinin • Cyclic induction of YFs was accompanied by improvement in object recognition test
In this article, Serrano, Ávila and colleagues show that cyclic expression of Yamanaka factors Oct4, Sox2, Klf4, and c-Myc in the hippocampus prevent the age-dependent reduction in the epigenetic marker H3K9 trimethylation (H3K9me3) and alter adult hippocampal neurogenesis. These cellular changes were accompanied by an improvement in mouse performance in the object recognition test.