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

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 1α. 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.

[1]  Brad E. Pfeiffer,et al.  Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long-Term Depression That Is Affected in Fragile X Syndrome Mental Retardation , 2007, The Journal of Neuroscience.

[2]  S. Warren,et al.  The pathophysiology of fragile x syndrome. , 2007, Annual review of genomics and human genetics.

[3]  C. Lüscher,et al.  Rapid Synthesis and Synaptic Insertion of GluR2 for mGluR-LTD in the Ventral Tegmental Area , 2007, Science.

[4]  O. Manzoni,et al.  Acute Stress Facilitates Hippocampal CA1 Metabotropic Glutamate Receptor-Dependent Long-Term Depression , 2007, The Journal of Neuroscience.

[5]  Christina Gross,et al.  Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome , 2007, The Journal of Neuroscience.

[6]  P. Worley,et al.  Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors , 2007, Proceedings of the National Academy of Sciences.

[7]  Richard Paylor,et al.  Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression , 2006, Neuron.

[8]  H. Cline,et al.  Visual Experience Regulates Metabotropic Glutamate Receptor-Mediated Plasticity of AMPA Receptor Synaptic Transmission by Homer1a Induction , 2006, The Journal of Neuroscience.

[9]  P. Worley,et al.  Homer proteins: implications for neuropsychiatric disorders , 2006, Current Opinion in Neurobiology.

[10]  M. Klugmann,et al.  Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain , 2006, Nature Medicine.

[11]  K. M. Huber,et al.  Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. , 2006, Journal of neurophysiology.

[12]  L. Volk,et al.  Differential roles for group 1 mGluR subtypes in induction and expression of chemically induced hippocampal long-term depression. , 2006, Journal of neurophysiology.

[13]  N. Sonenberg,et al.  Regulation of Eukaryotic Initiation Factor 4E by Converging Signaling Pathways during Metabotropic Glutamate Receptor-Dependent Long-Term Depression , 2006, The Journal of Neuroscience.

[14]  B. Oostra,et al.  A Reduced Number of Metabotropic Glutamate Subtype 5 Receptors Are Associated with Constitutive Homer Proteins in a Mouse Model of Fragile X Syndrome , 2005, The Journal of Neuroscience.

[15]  P. Koulen,et al.  Effects of Vesl/Homer Proteins on Intracellular Signaling , 2005, Experimental biology and medicine.

[16]  E. De Schutter,et al.  Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome , 2005, Neuron.

[17]  O. Steward,et al.  The mRNA for Elongation Factor 1α Is Localized in Dendrites and Translated in Response to Treatments That Induce Long-Term Depression , 2005, The Journal of Neuroscience.

[18]  Q. Tang,et al.  The Scaffold Protein Homer1b/c Links Metabotropic Glutamate Receptor 5 to Extracellular Signal-Regulated Protein Kinase Cascades in Neurons , 2005, The Journal of Neuroscience.

[19]  I. Weiler,et al.  Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Eric Klann,et al.  Activation of the Phosphoinositide 3-kinase–akt–mammalian Target of Rapamycin Signaling Pathway Is Required for Metabotropic Glutamate Receptor-dependent Long-term Depression , 2022 .

[21]  M. Bear,et al.  Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1 , 2004, The Journal of Neuroscience.

[22]  Peter K. Todd,et al.  The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  E. Nagata,et al.  PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis , 2003, Nature Neuroscience.

[24]  P. Worley,et al.  Homer as Both a Scaffold and Transduction Molecule , 2002, Science's STKE.

[25]  Mark F. Bear,et al.  Altered synaptic plasticity in a mouse model of fragile X mental retardation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Mark F. Bear,et al.  Internalization of ionotropic glutamate receptors in response to mGluR activation , 2001, Nature Neuroscience.

[27]  M. Bear,et al.  Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. , 2000, Science.

[28]  G. Thomas,et al.  Ribosomal S6 kinase signaling and the control of translation. , 1999, Experimental cell research.

[29]  P. Worley,et al.  Homer Regulates the Association of Group 1 Metabotropic Glutamate Receptors with Multivalent Complexes of Homer-Related, Synaptic Proteins , 1998, Neuron.

[30]  D. Linden,et al.  Homer Binds a Novel Proline-Rich Motif and Links Group 1 Metabotropic Glutamate Receptors with IP3 Receptors , 1998, Neuron.

[31]  G. R. Seabrook,et al.  The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus , 1997, Neuropharmacology.

[32]  I. Weiler,et al.  Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Barnes,et al.  Homer: a protein that selectively binds metabotropic glutamate receptors , 1997, Nature.