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Mol. Cell. Biol. doi:10.1128/MCB.00201-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

mGluR-dependent Long-term Depression is Associated with Increased Phosphorylation of S6 and Synthesis of EF1A, but Remains Expressed in S6K-deficient Mice

Departments of Neuroscience; and Molecular Physiology & Biophysics; Baylor College of Medicine, Houston, TX 77030, Center for Neural Science; New York University, New York, NY 10003

^* To whom correspondence should be addressed. Email: eklann{at}cns.nyu.edu.

	Abstract

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus requires rapid protein synthesis, which suggests that mGluR activation is coupled to signaling pathways that regulate translation. Herein, we have investigated the signaling pathways that couple group I mGluRs to ribosomal S6 protein phosphorylation and 5'oligopyrimidine tract-encoded protein (5'TOP) synthesis during mGluR-LTD. We found that mGluR-LTD was associated with increased phosphorylation of p70S6 kinase (S6K1) and S6, as well as the synthesis of the 5'TOP-encoded protein elongation factor 1A (EF1A). Moreover, we found that LTD-associated increases in S6K1 phosphorylation, S6 phosphorylation, and the levels of EF1A were sensitive to inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK). However, mGluR-LTD was normal in S6K1 knockout mice and enhanced in both S6K2 knockout mice and S6K1/S6K2 double-knockout mice. In addition, we observed that LTD-associated increases in S6 phosphorylation were still increased S6K1- and S6K2-deficient mice, whereas basal levels of EF1A were abnormally elevated. Taken together, these findings indicate that mGluR-LTD is associated with PI3K-, mTOR-, and ERK-dependent alterations in the phosphorylation of S6 and S6K. Our data also suggests that S6Ks are not required for the expression of mGluR-LTD and that the synthesis of 5'TOP-encoded proteins are independent of S6Ks during mGluR-LTD.