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Novel translational control in Arc-dependent long term potentiation consolidation in vivo.

ABSTRACT: Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2alpha on a protracted time course matching the time-window of Arc translation. Local infusion of the ERK inhibitor U0126 inhibited LTP maintenance and Arc protein expression, blocked changes in eIF4E and eIF2alpha phosphorylation state, and prevented initiation complex (eIF4F) formation. Surprisingly, inhibition of the mTOR protein complex 1 (mTORC1) with rapamycin did not impair LTP maintenance or Arc synthesis nor did it inhibit eIF4F formation or phosphorylation of eIF4E. Rapamycin nonetheless blocked mTOR signaling to p70 S6 kinase and ribosomal protein S6 and inhibited synthesis of components of the translational machinery. Using immunohistochemistry and in situ hybridization, we show that Arc protein expression depends on dual, ERK-dependent transcription and translation. Arc translation is selectively blocked by pharmacological inhibition of mitogen-activated protein kinase-interacting kinase (MNK), the kinase coupling ERK to eIF4E phosphorylation. Furthermore, MNK signaling was required for eIF4F formation. These results support a dominant role for ERK-MNK signaling in control of translational initiation and Arc synthesis during LTP consolidation in the dentate gyrus. In contrast, mTORC1 signaling is activated but nonessential for Arc synthesis and LTP. The work, thus, identifies translational control mechanisms uniquely tuned to Arc-dependent LTP consolidation in live rats.

SUBMITTER: Panja D

PROVIDER: S-EPMC2797219 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Novel translational control in Arc-dependent long term potentiation consolidation in vivo.

Panja Debabrata D Dagyte Girstaute G Bidinosti Michael M Wibrand Karin K Kristiansen Ase-Marit AM Sonenberg Nahum N Bramham Clive R CR

The Journal of biological chemistry 20090915 46

Regulation of translation factor activity plays a major role in protein synthesis-dependent forms of synaptic plasticity. We examined translational control across the critical period of Arc synthesis underlying consolidation of long term potentiation (LTP) in the dentate gyrus of intact, anesthetized rats. LTP induction by high frequency stimulation (HFS) evoked phosphorylation of the cap-binding protein eukaryotic initiation factor 4E (eIF4E) and dephosphorylation of eIF2alpha on a protracted t ...[more]

PMID: 19755425

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Project description:Coordinated regulation of gene expression is essential for consolidation of the memory mechanism, long-term potentiation (LTP). Triggering of LTP by N-methyl-D-aspartate receptor (NMDAR) activation rapidly activates constitutive and inducible transcription factors, which promote expression of genes responsible for LTP maintenance. As microRNA (miRNA) coordinate expression of genes related through seed sites, we hypothesize that miRNA contribute to the regulation of the LTP-induced gene response. MiRNA function primarily as negative regulators of gene expression. As LTP induction promotes a generalized rapid up-regulation of gene expression, we predicted a complementary rapid down-regulation of miRNA levels. Accordingly, we carried out global miRNA expression profiling in the rat dentate gyrus 20 min post-LTP induction in vivo. Consistent with our hypothesis, we found a large number of differentially expressed miRNA, the majority down-regulated. Detailed analysis of miR-34a-5p and miR-132-3p revealed this down-regulation was transient and NMDAR-dependent, whereby block of NMDARs released an activity-associated inhibitory mechanism. Furthermore, down-regulation of mature miR-34a-5p and miR-132-3p occurred solely by post-transcriptional mechanisms, occurring despite an associated up-regulation of the pri-miR-132 transcript. To understand how down-regulation of miR-34a-5p and miR-132-3p intersects with the molecular events occurring following LTP, we used bioinformatics to identify potential targets. Previously validated targets included the key LTP-regulated genes Arc and glutamate receptor subunits. Predicted targets included the LTP-linked kinase, Mapk1, and neuropil-associated transcripts Hn1 and Klhl11, which were validated using luciferase reporter assays. Furthermore, we found that the level of p42-Mapk1, the protein encoded by the Mapk1 transcript, was up-regulated following LTP. Together, these data support the interpretation that miRNA, in particular miR-34a-5p and miR-132-3p, make a surprisingly rapid contribution to synaptic plasticity via dis-inhibition of translation of key plasticity-related molecules.

Dataset Information

Novel translational control in Arc-dependent long term potentiation consolidation in vivo.

Publications

Novel translational control in Arc-dependent long term potentiation consolidation in vivo.

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