title: Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.
abstract: Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease.
  
  
  CONCLUSIONS
  Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders.
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, Texas 75390.
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, Texas 75390.
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, Texas 75390.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Collins
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, Texas 75390.
authors.forename: Seth A
authors.identifier: http://orcid.org/0000-0003-4225-241X
authors.initials: SA
authors.lastname: Hays
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California, Santa Barbara, California 93106.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.affiliation: University of Texas Southwestern Medical Center, Department of Neuroscience, Dallas, Texas 75390, Kimberly.Huber@UTSouthwestern.edu.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology*; D055879:Gene Knock-In Techniques; D000072233:Homer Scaffolding Proteins; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000378:metabolism; D010641:Phenotype; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics*; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D055139:Sensory Gating
chemical_list: D002352:Carrier Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D000072233:Homer Scaffolding Proteins; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse
keywords: Homer; LTD; UP states; fragile X syndrome; mGluR5; protein synthesis