title: Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning.
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.
authors.affiliation: Sagol Department of Neurobiology.
authors.forename: Hadile
authors.initials: H
authors.lastname: Ounallah-Saad
authors.affiliation: Sagol Department of Neurobiology.
authors.forename: Vijendra
authors.identifier: http://orcid.org/0000-0002-0945-2623
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Center for Gene Manipulation in the Brain, University of Haifa, Haifa 3498838, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Edry
authors.affiliation: Sagol Department of Neurobiology, Center for Gene Manipulation in the Brain, University of Haifa, Haifa 3498838, Israel kobir@psy.haifa.ac.il.
authors.forename: Kobi
authors.initials: K
authors.lastname: Rosenblum
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering; D051381:Rats; D013649:Taste / Q000187:drug effects / Q000502:physiology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000225:Adenine; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D034741:RNA, Small Interfering; D019892:eIF-2 Kinase; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
keywords: consolidation; eIF2α; gustatory cortex; protein synthesis; taste