EZH2 methyltransferase activity controls pten expression and mTOR signaling during fear memory reconsolidation

Academic Article

Abstract

  • © 2018 the authors. Memory retrieval induces a transient period of increased transcriptional and translational regulation in neurons called reconsolidation, which is regulated by the protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathway. However, it is currently unknown how activation of the AKT–mTOR pathway is regulated during the reconsolidation process. Here, we found that in male rats retrieval of a contextual fear memory transiently increased Enhancer of Zeste Homolog 2 (EZH2) levels along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, which correlated with decreased levels of phosphatase and tensin homolog (PTEN), a potent inhibitor of AKT–mTOR-dependent signaling in the hippocampus. Further experiments found increased H3K27me3 levels and DNA methylation across the Pten promoter and coding regions, indicating transcriptional silencing of the Pten gene. Pten H3K27me3 levels did not change following training or after the retrieval of a remote (old) fear memory, suggesting that this mechanism of Pten repression was specific to the reconsolidation of a new memory. In vivo siRNA-mediated knockdown of Ezh2 in the hippocampus abolished retrieval-induced increases in H3K27me3 and prevented decreases in PTEN levels. Ezh2 knockdown attenuated increases in the phosphorylation of AKT and mTOR following retrieval, which could be restored by simultaneously reducing Pten, suggesting that H3K27me3 regulates AKT– mTOR phosphorylation via repression of Pten. Consistent with these results, knockdown of Ezh2 in area CA1 before retrieval impaired memory on later tests. Collectively, these results suggest that EZH2-mediated H3K27me3 plays a critical role in the repression of Pten transcription necessary for AKT–mTOR activation and memory reconsolidation following retrieval.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Jarome TJ; Perez GA; Hauser RM; Hatch KM; Lubin FD
  • Start Page

  • 7635
  • End Page

  • 7648
  • Volume

  • 38
  • Issue

  • 35