Abstract
Protein translation initiation is controlled by levels of eIF2α phosphorylation (p-eIF2α) on Ser51. In addition, increased p-eIF2α levels impair long-term synaptic plasticity and memory consolidation, whereas decreased levels enhance them. Levels of p-eIF2α are determined by four kinases, of which protein kinase RNA-activated (PKR), PKR-like endoplastic reticulum kinase (PERK), and general control nonderepressible 2 are extensively expressed in the mammalian mature brain. Following identification of PERK as the major kinase to determine basal levels of p-eIF2α in primary neuronal cultures, we tested its function as a physiological constraint of memory consolidation in the cortex, the brain structure suggested to store, at least in part, long-term memories in the mammalian brain. To that aim, insular cortex (IC)-dependent positive and negative forms of taste learning were used. Genetic reduction of PERK expression was accomplished by local microinfusion of a lentivirus harboring PERK Short hairpin RNA, and pharmacological inhibition was achieved by local microinfusion of a PERK-specific inhibitor (GSK2606414) to the rat IC. Both genetic reduction of PERK expression and pharmacological inhibition of its activity reduced p-eIF2α levels and enhanced novel taste learning and conditioned taste aversion, but not memory retrieval. Moreover, enhanced extinction was observed together with enhanced associative memory, suggesting increased cortical- dependent behavioral plasticity. The results suggest that, by phosphorylating eIF2α, PERK functions in the cortex as a physiological constraint of memory consolidation, and its downregulation serves as cognitive enhancement.
Original language | English |
---|---|
Pages (from-to) | 14624-14632 |
Number of pages | 9 |
Journal | Journal of Neuroscience |
Volume | 34 |
Issue number | 44 |
DOIs | |
State | Published - 29 Oct 2014 |
Bibliographical note
Publisher Copyright:© 2014 the authors.
Keywords
- Consolidation
- EIF2α
- Gustatory cortex
- Protein synthesis
- Taste
ASJC Scopus subject areas
- General Neuroscience