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J Neurosci. 2014 Oct 29;34(44):14624-32. doi: 10.1523/JNEUROSCI.2117-14.2014.

Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning.

Author information

1
Sagol Department of Neurobiology.
2
Center for Gene Manipulation in the Brain, University of Haifa, Haifa 3498838, Israel.
3
Sagol Department of Neurobiology, Center for Gene Manipulation in the Brain, University of Haifa, Haifa 3498838, Israel kobir@psy.haifa.ac.il.

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.

KEYWORDS:

consolidation; eIF2α; gustatory cortex; protein synthesis; taste

PMID:
25355215
DOI:
10.1523/JNEUROSCI.2117-14.2014
[Indexed for MEDLINE]
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