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Molecular and Cellular Biology, May 2008, p. 2996-3007, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.00201-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

mGluR-Dependent Long-Term Depression Is Associated with Increased Phosphorylation of S6 and Synthesis of Elongation Factor 1A but Remains Expressed in S6K-Deficient Mice{triangledown}

Marcia D. Antion,1,{dagger} Lingfei Hou,2,3 Helen Wong,3 Charles A. Hoeffer,2,3 and Eric Klann1,2,3*

Departments of Neuroscience,1 Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030,2 Center for Neural Science, New York University, New York, New York 100033

Received 7 February 2008/ Accepted 20 February 2008

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 (5'TOP)-encoded protein 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 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 in 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 suggest that S6Ks are not required for the expression of mGluR-LTD and that the synthesis of 5'TOP-encoded proteins is independent of S6Ks during mGluR-LTD.

* Corresponding author. Mailing address: Center for Neural Science, New York University, 4 Washington Place, Room 809, New York, NY 10003. Phone: (212) 992-9769. Fax: (212) 995-4011. E-mail: eklann{at}cns.nyu.edu

{triangledown} Published ahead of print on 3 March 2008.

{dagger} Present address: Department of Physiology, Northwestern University School of Medicine, Ward 7-275, 303 E. Chicago Ave., Chicago, IL 60611.

Molecular and Cellular Biology, May 2008, p. 2996-3007, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.00201-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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