title: Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome.
abstract: Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model, Fmr1 knockout (Fmr1(-/y)). In Fmr1(-/y) mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5-long Homer scaffolds and corrected several phenotypes in Fmr1(-/y) mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many Fmr1(-/y) phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of Fmr1. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Ronesi
authors.forename: Katie A
authors.initials: KA
authors.lastname: Collins
authors.forename: Seth A
authors.initials: SA
authors.lastname: Hays
authors.forename: Nien-Pei
authors.initials: NP
authors.lastname: Tsai
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Hu
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Jay R
authors.initials: JR
authors.lastname: Gibson
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D000072233:Homer Scaffolding Proteins; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D010825:Physics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003513:Cycloheximide; D051860:Fragile X Messenger Ribonucleoprotein 1; D000072233:Homer Scaffolding Proteins; D008734:Methoxyhydroxyphenylglycol; D010455:Peptides; D011500:Protein Synthesis Inhibitors; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012694:Serine; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; C546843:mTOR protein, mouse; C010117:3,4-dihydroxyphenylglycol