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

• Published in: The Journal of neuroscience Vol. 28; no. 2; pp. 543 - 547
• Main Authors: Ronesi, Jennifer A, Huber, Kimberly M
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 09-01-2008; Society for Neuroscience
• Subjects: Analysis of Variance; Animals; Brief Communications; Carrier Proteins - physiology; Dose-Response Relationship, Radiation; Electric Stimulation; Fragile X Mental Retardation Protein - genetics; Gene Expression Regulation - physiology; Hippocampus - cytology; Homer Scaffolding Proteins; In Vitro Techniques; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Long-Term Synaptic Depression - radiation effects; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - drug effects; Neurons - physiology; Neurons - radiation effects; Patch-Clamp Techniques - methods; Peptides - pharmacology; Protein Biosynthesis - drug effects; Protein Biosynthesis - physiology; Protein Biosynthesis - radiation effects; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - chemistry; Receptors, Metabotropic Glutamate - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Signal Transduction - radiation effects
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5019-07.2008

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 1alpha. 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.