PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility

PLoS One. 2016 Sep 14;11(9):e0162766. doi: 10.1371/journal.pone.0162766. eCollection 2016.

Abstract

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for memory flexibility and metabotropic glutamate receptor-dependent long-term depression, processes known to be dependent on new protein synthesis. Here we investigated PERK's role in working memory, a cognitive ability that is independent of new protein synthesis, but instead is dependent on cellular Ca2+ dynamics. We found that working memory is impaired in forebrain-specific Perk knockout and pharmacologically PERK-inhibited mice. Moreover, inhibition of PERK in wild-type mice mimics the fear extinction impairment observed in forebrain-specific Perk knockout mice. Our findings reveal a novel role of PERK in cognitive functions and suggest that PERK regulates both Ca2+ -dependent working memory and protein synthesis-dependent memory flexibility.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Blotting, Western
  • Extinction, Psychological / physiology
  • Indoles / pharmacology
  • Maze Learning / physiology
  • Memory, Short-Term
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / biosynthesis
  • Prosencephalon / metabolism
  • Prosencephalon / physiology
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / physiology*

Substances

  • 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
  • Indoles
  • Nerve Tissue Proteins
  • PERK kinase
  • eIF-2 Kinase
  • Adenine