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The Journal of Neuroscience, February 22, 2006, 26(8):2167-2173; doi:10.1523/JNEUROSCI.5196-05.2006

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Brief Communications
Regulation of Eukaryotic Initiation Factor 4E by Converging Signaling Pathways during Metabotropic Glutamate Receptor-Dependent Long-Term Depression

Jessica L. Banko,^1 * Lingfei Hou,^1 * Francis Poulin,³ Nahum Sonenberg,³ and Eric Klann^1,2

¹Departments of Molecular Physiology and Biophysics and ²Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and ³Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6

Correspondence should be addressed to Dr. Eric Klann, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030. Email: eklann{at}bcm.tmc.edu

Long-term depression (LTD) is an activity-dependent decrease in synaptic efficacy that can be induced in hippocampal area CA1 by pharmacological application of the selective group I metabotropic glutamate receptor (mGluR) agonist 3,5-diyhroxyphenylglycine (DHPG). Recent work has demonstrated that DHPG-induced LTD recruits at least two signal transduction pathways known to couple to translation, the mitogen-activated protein kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling pathway and the phosphoinositide 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling pathway. However, it remains unclear which translation factors are engaged by these two signaling pathways during mGluR-LTD. In this study, we investigated whether the group I mGluRs couple to the cap-dependent translation proteins: Mnk1, eIF4E, and 4E-BP. We found that both the MEK–ERK and PI3K–mTOR signaling pathways are critical for the DHPG-induced regulation of these translation factors. Furthermore, we demonstrate that increasing eIF4F complex availability via the genetic elimination of 4E-BP2 can enhance the degree of LTD achieved by DHPG application in an ERK-dependent manner. Our results provide direct evidence that cap-dependent translation is engaged during mGluR-LTD and demonstrate that the MEK–ERK and PI3K–mTOR signaling pathways converge to regulate eIF4E activity after induction of DHPG-LTD.

Key words: protein synthesis; hippocampus; mGluR; ERK; synaptic plasticity; PI3 kinase

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Received Aug. 1, 2005; accepted Jan. 6, 2006.

Correspondence should be addressed to Dr. Eric Klann, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030. Email: eklann{at}bcm.tmc.edu

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