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Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning
Hadile Ounallah-Saad1, Vijendra Sharma1, Efrat Edry2
1Sagol Department of Neurobiology.
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.
Insights
Reducing protein kinase R-like endoplasmic reticulum kinase (PERK) activity enhances memory consolidation and behavioral plasticity in the cortex. This suggests PERK acts as a constraint on memory, and its downregulation offers cognitive enhancement.
Area of Science:
- Neuroscience
- Molecular Biology
- Cognitive Science
Background:
- Protein translation initiation is regulated by eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation (p-eIF2α) at Ser51.
- p-eIF2α levels influence long-term synaptic plasticity and memory consolidation; higher levels impair, while lower levels enhance these processes.
- Key kinases determining p-eIF2α levels in the mature mammalian brain include protein kinase RNA-activated (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2.
Purpose of the Study:
- To investigate the role of PERK as a physiological constraint on memory consolidation in the mammalian cortex.
- To determine if reducing PERK activity enhances cortical-dependent learning and memory.
Main Methods:
- PERK's role was assessed in insular cortex (IC)-dependent taste learning paradigms in rats.
- Genetic reduction of PERK expression was achieved using lentivirus-mediated short hairpin RNA (shRNA) microinfusion into the rat IC.
- Pharmacological inhibition of PERK activity was performed via microinfusion of a specific inhibitor (GSK2606414) into the rat IC.
Main Results:
- Both genetic PERK reduction and pharmacological inhibition decreased p-eIF2α levels in the IC.
- These interventions enhanced novel taste learning and conditioned taste aversion, indicating improved memory formation.
- Memory retrieval was unaffected, but enhanced extinction of learned behaviors was observed, suggesting increased behavioral plasticity.
Conclusions:
- PERK, through eIF2α phosphorylation, acts as a physiological constraint on memory consolidation within the cortex.
- Downregulation of PERK activity in the cortex leads to cognitive enhancement, specifically improving learning and behavioral plasticity.
- These findings highlight PERK as a potential therapeutic target for cognitive enhancement.
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