Genetic or Pharmacological Reduction of PERK Enhances Cortical-Dependent Taste Learning

Abstract

Protein translation initiation is controlled by levels of eIF2␣ phosphorylation (p-eIF2␣) on Ser51. In addition, increased p-eIF2␣ levels impair long-term synaptic plasticity and memory consolidation, whereas decreased levels enhance them. Levels of p-eIF2␣ 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-eIF2␣ 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-eIF2␣ 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 corticaldependent behavioral plasticity. The results suggest that, by phosphorylating eIF2␣, PERK functions in the cortex as a physiological constraint of memory consolidation, and its downregulation serves as cognitive enhancement.

Translational control by eIF2α in neurons: Beyond the stress response

“…A specific PERK disruption in the adult mouse forebrain, decreases eIF2α phosphorylation and ATF4 expression, which was associated to behavioral perseveration, decreased prepulse inhibition, reduced fear extinction and impaired behavioral flexibility [Trinh et al, ]. Furthermore, inhibition of PERK by the use of shRNAs or a chemical inhibitor infused in the insular cortex of rats reduced phosphorylated eIF2α levels and enhanced learning in a taste‐based memory test [Ounallah‐Saad et al, ]. The ablation of PKR by genetic modification or chemical inhibition facilitates LTP formation in cell models and increased learning in the Morris water maze, auditory fear memory [Zhu et al, ] and taste learning paradigm [Stern et al, ].…”

Translational control of auditory imprinting and structural plasticity by eIF2α

“…A major way in which translation initiation is regulated is by modulating the formation of the ternary complex via phosphorylation of the translation-initiation factor eIF2α. In rodents, protein synthesis controlled by phosphorylation of eIF2α is critically required for long-lasting forms of synaptic plasticity (Costa-Mattioli et al, 2007; Di Prisco et al, 2014) as well as long-term memory storage in several systems (Costa-Mattioli et al, 2007, 2005; Zhu et al, 2011; Stern et al, 2013; Ounallah-Saad et al, 2014; Ma et al, 2013). Here we asked whether this central translational control mechanism plays a role in imprinting in newborn chickens and can be used to restore imprinting outside of the CP.…”

Measuring mRNA translation in neuronal processes and somata by tRNA-FRET

“…P1 neonatal C57BL/6 and Arc:dVenus mouse cortices were used to prepare primary cultures as previously described in (61). Primary cultures were seeded in nonpyrogenic polystyrene cell culture plates (Corning, Corning, NY).…”

“…At the same time, dysregulation of these mechanisms underlies various neurodevelopmental and neurodegenerative pathologies. Both the initiation and elongation phases of mRNA translation and the respective translation factors that mediate them have been suggested as innovative targets for memory enhancement in health and disease (56,(59)(60)(61)(62)(63)111).…”