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1.  Translational Control by eIF2α Kinases in Long-lasting Synaptic Plasticity and Long-term Memory 
Although the requirement for new protein synthesis in synaptic plasticity and memory has been well established, recent genetic, molecular, electrophysiological, and pharmacological studies have broadened our understanding of the translational control mechanisms that are involved in these processes. One of the critical translational control points mediating general and gene-specific translation depends on the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by four regulatory kinases. Here, we review the literature highlighting the important role for proper translational control via regulation of eIF2α phosphorylation by its kinases in long-lasting synaptic plasticity and long-term memory.
doi:10.1016/j.nlm.2013.04.013
PMCID: PMC3769507  PMID: 23707798
protein synthesis; translation initiation; synaptic plasticity; learning; memory; knockout mouse; eIF2; GCN2; PERK; PKR; HRI
2.  Suppression of eIF2α kinases alleviates AD-related synaptic plasticity and spatial memory deficits 
Nature neuroscience  2013;16(9):1299-1305.
Expression of long-lasting synaptic plasticity and long-term memory requires new protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2α subunit (eIF2α). It was reported previously that eIF2α phosphorylation is elevated in the brains of Alzheimer’s disease (AD) patients and AD model mice. Therefore, we determined whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in AD model mice. The genetic deletion of the eIF2α kinase PERK prevented enhanced eIF2α phosphorylation, as well as deficits in protein synthesis, synaptic plasticity, and spatial memory in APP/PS1 AD model mice. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and spatial memory defects displayed in the APP/PS1 mice. Our findings implicate aberrant eIF2α phosphorylation as a novel molecular mechanism underlying AD-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for the treatment of individuals with AD.
doi:10.1038/nn.3486
PMCID: PMC3756900  PMID: 23933749
3.  Brain-specific Disruption of the eIF2α Kinase PERK Decreases ATF4 Expression and Impairs Behavioral Flexibility 
Cell Reports  2012;1(6):676-688.
Summary
Translational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α phosphorylation and ATF4 expression were diminished and associated with enhanced behavioral perseveration, decreased prepulse inhibition, reduced fear extinction, and impaired behavioral flexibility. Treatment with the glycine transporter inhibitor SSR504734 normalized eIF2α phosphorylation, ATF4 expression, and behavioral flexibility in PERK-deficient mice. Moreover, PERK and ATF4 expression were reduced in the frontal cortex of human schizophrenic patients. Together, our findings reveal that PERK plays a critical role in information processing and cognitive function, and that modulation of eIF2α phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders including schizophrenia.
doi:10.1016/j.celrep.2012.04.010
PMCID: PMC3401382  PMID: 22813743
PERK; translational control; eIF2α; ATF4; prefrontal cortex; cognitive control; glycine transporter-1 inhibitor; behavioral flexibility; schizophrenia

Results 1-3 (3)