The mRNA for Elongation Factor 1α Is Localized in Dendrites and Translated in Response to Treatments That Induce Long-Term Depression

Abstract

There is increasing evidence that long-lasting forms of activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), require local synthesis of proteins within dendrites. Identifying novel dendritic mRNAs and determining how their distribution and translation is regulated is a high priority. We demonstrate here that the mRNA for the elongation factor 1 alpha (EF1alpha) is present in vivo in the dendrites of neurons that exhibit LTP and LTD, and that its translation is locally regulated. The subcellular distribution of EF1alpha mRNA differs from any of the dendritic mRNAs that have been described previously. In the hippocampus, the mRNA is highly expressed in cell bodies and is also concentrated in the zone of termination of commissural/associational afferents in the inner molecular layer, suggesting that mRNA localization is in some way related to the distribution of different types of synapses. Nevertheless, the localization of EF1alpha mRNA is not altered by prolonged periods of synaptic activation that are sufficient to cause a dramatic redistribution of Arc mRNA. Local application of the metabotropic glutamate receptor agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) led to dramatic increases in immunostaining for EF1alpha protein in dendrites, and treatment of hippocampal slices with DHPG, which is known to induce LTD, led to increases in EF1alpha protein levels. Both responses were blocked by the protein synthesis inhibitor anisomycin. In contrast, stimulation of the perforant path using patterns of stimulation that induce LTP caused rapid increases of immunostaining for EF1alpha protein in the activated dendritic lamina, but these increases were not blocked by anisomycin or rapamycin. The findings suggest that local synthesis of EF1alpha protein may be important for the synaptic mechanisms that underlie protein synthesis-dependent LTD.

Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate GyrusIn Vivo

“…Because such inhibitors perturb cell metabolism and have variable effects on the translation of some dendritic mRNAs (Wallace et al, 1998;Steward and Halpain, 1999;Huang et al, 2005;Routtenberg and Rekart, 2005), their actions may not accurately reflect the contribution of activity-induced protein synthesis to LTP. By specifically targeting Arc synthesis, we revealed a novel dynamic in LTP maintenance of the dentate gyrus.…”

“…First, it is well known the protein synthesis inhibitors have deleterious effects on cellular metabolism and homeostasis (Klann and Dever, 2004;Routtenberg and Rekart, 2005). Second, several studies of synaptic plasticity report maintained or enhanced synthesis of dendritically localized mRNAs [Arc, ␣-CaMKII, and EF1A (elongation factor 1A)] in the presence of protein synthesis inhibitors (Hughes et al, 1997;Steward and Halpain, 1999;Huang et al, 2005) or during global translation arrest (Scheetz et al, 2000;Chotiner et al, 2003). In general, treatment with protein synthesis inhibitors before HFS cause a slowing decaying LTP, whereas treatment during LTP maintenance has no effect.…”

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…78 Notably, a number of studies have documented an elevation in the levels of elongation factors eEF1A and eEF2, as well as ribosomal protein S6, in response to synaptic activity in both mammals and Aplysia. [83][84][85][86][87][88] All of these proteins are encoded by TOP mRNAs, 64 suggesting that mTORC1 may participate in synaptic plasticity by locally increasing the availability of translation factors and other components of the translational apparatus. 78 Evidence for this comes from the observation that TOP mRNAs are transported into dendrites and axons where they are locally translated in an mTORC1-dependent manner.…”

The Role of Protein Synthesis in Striatal Long-Term Depression

“…Because previous work has implicated postsynaptic translation in long-term synaptic plasticity (Huber et al, 2000;Huang et al, 2005), it is important to examine possible involvement of postsynaptic translation in striatal LTD. Using whole-cell recording, we further investigated the site of protein synthesis necessary for LTD. We compared effects of bath application of cycloheximide (80 M) with postsynaptic intracellular loading of this translation inhibitor at the same concentration ( Fig.…”

“…Although the role of dendritic protein translation in longterm plasticity is widely accepted, axons are not traditionally thought to be sites of protein synthesis (Huber et al, 2000;Martin, 2004;Huang et al, 2005;Tsokas et al, 2005). Strong evidence, however, has emerged in recent years showing local translation of proteins from existing mRNAs in the axon (Alvarez et al, 2000;Campenot and Eng, 2000;Piper and Holt, 2004).…”