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The Journal of Neuroscience, January 9, 2008, 28(2):543-547; doi:10.1523/JNEUROSCI.5019-07.2008

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Brief Communications
Homer Interactions Are Necessary for Metabotropic Glutamate Receptor-Induced Long-Term Depression and Translational Activation

Jennifer A. Ronesi and Kimberly M. Huber

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Dr. Kimberly M. Huber, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, NA4.118, Dallas, TX 75390-9011. Email: kimberly.huber{at}utsouthwestern.edu

Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1 knock-out (KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type and Fmr1 KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR–Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5' terminal oligopyrimidine tract containing mRNA, Elongation factor 1. In Fmr1 KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR–Homer interactions in Fmr1 KO mice lead to a deficit in mGluR stimulation of translation initiation.

Key words: Homer; group I mGluRs; long-term depression; translation; PI3K; mTOR; Fragile X

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Received Sept. 6, 2007; revised Dec. 4, 2007; accepted Dec. 6, 2007.

Correspondence should be addressed to Dr. Kimberly M. Huber, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, NA4.118, Dallas, TX 75390-9011. Email: kimberly.huber{at}utsouthwestern.edu

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