Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice

Abstract

Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.

Consolidation and translation regulation: Figure 1.

“…The role of eEF2 phosphorylation in processing associative memory at the systems level was also examined using manganese-enhanced magnetic resonance imaging (MEMRI). eEF2K-deficient mice had a more diffuse accumulation of Mn 2+ following CTA acquisition as compared with wild-type mice (Gildish et al 2012), suggesting that the regulation of eEF2 participates in the regulation of brain activation patterns during associative memory formation.…”

“…Currently, the term consolidation or off-line processing of a given memory consists of two distinct processes: aspects of molecular consolidation, completed within hours after training, and system consolidation, taking several days or more, and thought to involve reorganization of brain circuits. However, the relationship between the two types of consolidation is poorly understood (Gildish et al 2012).…”

“…Following incidental taste learning, eEF2 phosphorylation increases within 20 min in the GC (Belelovsky et al 2005;Gildish et al 2012). In addition, transgenic mice that express a kinase-defective version of eEF2K and have significantly diminished levels of p-eEF2 are impaired in CTA learning, but not incidental taste learning, suggesting that the regulation of eEF2 phosphorylation is important specifically for associative taste memories (Gildish et al 2012). The role of eEF2 phosphorylation in processing associative memory at the systems level was also examined using manganese-enhanced magnetic resonance imaging (MEMRI).…”

Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

“…Park et al [59] showed that eEF2K plays an important role in the synthesis of Arc/Arg3.1, a protein involved in neurotransmitter receptor trafficking and in longterm depression, a process that reflects changes in synaptic strength. Gildish et al [60] used mice in which an inactivating mutation was introduced into the eEF2K gene. Their data showed that such animals displayed defective associative taste learning in a learning paradigm termed conditioned taste aversion.…”

A recollection of mTOR signaling in learning and memory

“…Critically, eEF2K is activated by calcium/calmodulin and consequently regulated by neural activity (Nairn et al 2001). Indeed, eEF2K has been implicated as a control point in the synthesis of proteins important for memory since either increasing or decreasing eEF2K activity affects memory formation in distinct plasticity paradigms (Im et al 2009;Gildish et al 2012). eEF2K has been shown to be particularly important in conveying information mediated by spontaneous release (Sutton et al 2007) and signaling though mGluR receptors (Park et al 2008).…”