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

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 DH...

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Published in:The Journal of neuroscience 2006-02, Vol.26 (8), p.2167-2173
Main Authors: Banko, Jessica L, Hou, Lingfei, Poulin, Francis, Sonenberg, Nahum, Klann, Eric
Format: Article
Language:English
Subjects:
Animals
Brief Communications
Cells, Cultured
Eukaryotic Initiation Factor-4E - metabolism
Gene Expression Regulation - physiology
Hippocampus - metabolism
Long-Term Synaptic Depression - physiology
Male
Mice
Mice, Inbred C57BL
Receptors, Metabotropic Glutamate - metabolism
Signal Transduction - physiology
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5196-05.2006