Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD

Abstract

SUMMARY Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca2+/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.

BDNF-induced local protein synthesis and synaptic plasticity

“…This alteration in eEF2 phosphorylation at Thr56 is typically associated with a reduction in the interaction of the elongation factor with ribosomes, thereby decreasing global protein synthesis (Nairn and Palfrey, 1987;Ryazanov et al, 1991Ryazanov et al, , 1988, but an increase in the translation of some dendritic mRNAs (e.g. aCaMKII and Arc) has also been reported (Belelovsky et al, 2005;Chotiner et al, 2003;Marin et al, 1997;Park et al, 2008;Scheetz et al, 2000). However, in contrast with the results obtained following injection of BDNF in the dentate gyrus, the neurotrophin was without effect on eEF2 phosphorylation in synaptoneurosomes isolated from the same region, suggesting that the arresting of elongation may be limited to non-synaptic sites.…”

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…For example, activity-regulated cytoskeletal associated (Arc) protein is synthesized within dendrites in an activity-and group I mGluR-dependent manner where it associates with components of AMPAR endocytosis machinery and has been shown to actively maintain LTD (Park et al, 2008;Waung et al, 2008). Within striatal regions, Arc protein expression is robustly induced following re-exposure to cocaine-paired stimuli and modulates extinction of drugseeking behavior (Hearing et al, 2011;Hearing et al, 2008).…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…This mechanism appears to be compromised in FXS, because reduced levels of FMRP were shown to lead to increased mGlu 5 -mediated GluA endocytosis in rat hippocampal neurons (Nakamoto et al, 2007). The mGlu 1/5 -dependent translational induction of two FMRP targets, Arc/Arg3.1 and MAP1B, which were suggested to be involved in activity-regulated GluA endocytosis in hippocampal neurons (Davidkova and Carroll, 2007;Waung et al, 2008), is absent in Fmr1 KO mice Park et al, 2008). Waung and Huber (2009) thus hypothesized that in the absence of the translational repressor FMRP, several 'LTD-proteins' are already present in excess at the synapse before LTD-inducing stimuli and could contribute to the exaggerated LTD phenotype.…”