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

Abstract

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.

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

“…First, translation is required as several general protein synthesis inhibitors block mGluR-LTD (Huber et al 2000). Second, pharmacological and genetic disruption of PI3K, mTORC1, and ERK signaling pathways alter the phosphorylation of multiple initiation factors and prevent the expression of normal mGluR-LTD (Gallagher et al 2004;Hou and Klann 2004;Banko et al 2006;Ronesi and Huber 2008). For example, mice lacking 4E-BP2, a translational repressor of eIF4F complex assembly, display enhanced mGluR-LTD (Banko et al 2006), suggesting that repression of translation initiation normally limits the magnitude of mGluR-LTD.…”

“…Activation of metabotropic glutamate receptor (mGluR)-dependent signaling is tightly coupled to the regulation of translation in hippocampal neurons (Huber et al 2000;Aschrafi et al 2005;Banko et al 2006;Ronesi and Huber 2008). Because the regulation of translation initiation involves eIF2a phosphorylation by PERK, we determined whether genetic disruption of PERK in the hippocampus impacted mGluR-LTD. Hippocampal slices from PERK cKO and wild-type mice were incubated with DHPG (50 mM, 10 min) to induce protein synthesis-dependent mGluR-LTD.…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Black arrows indicate how upstream membrane receptors activate and/or regulate some of the downstream targets, illustrating crosstalk between pathways and putative shared dysregulated downstream mechanisms: MMP-9 was suggested to be regulated by mGlu 1/5 signaling (Bilousova et al, 2009) and by GABAergic signaling via an ERK-dependent mechanism (Miao et al, 2010). ERK1/2 and PI3K are regulated by mGlu 1/5 (Banko et al, 2006) and by TrkB signaling (Yoshii and Constantine-Paton, 2010). ERK1/2 was shown to signal downstream of D 1/5 (Beaulieu and Gainetdinov, 2011).…”

“…These findings also suggest that FMRP might control shared signaling molecules that are key players to regulate neurotransmitter-mediated signaling and protein synthesis. The two major pathways regulating neurotransmitter-induced protein synthesis in neurons are the ERK1/2 and the PI3K/mTOR (mammalian target of rapamycin) pathways (Banko et al, 2006;Nagai et al, 2007;Schicknick et al, 2008;Santos et al, 2010;Zhou et al, 2010). Both pathways also play crucial roles for intracellular signaling, and many of the above discussed dysregulated neurotransmitter-dependent signaling mechanisms in FXS are regulated or mediated via ERK1/2 and/or PI3K signaling (Figure 1).…”

Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited 10 years later

“…Thus, the phosphorylation of 4E-BP1 and S6 in neurons is regulated by the ERK pathway and has been shown to play a major role in LTP (Kelleher et al, 2004a). Other inhibitory eIF4E-binding proteins, such as 4E-BP2, can also play a critical role in the translational control of L-LTP and L-LTD (Banko et al, 2006;Banko et al, 2005).…”