Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome

• Published in: Nature neuroscience Vol. 15; no. 3; pp. 431 - 440
• Main Authors: Ronesi, Jennifer A, Collins, Katie A, Hays, Seth A, Tsai, Nien-Pei, Guo, Weirui, Birnbaum, Shari G, Hu, Jia-Hua, Worley, Paul F, Gibson, Jay R, Huber, Kimberly M
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2012
• Subjects: Analysis of Variance; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cycloheximide - pharmacology; Disease Models, Animal; Electric Stimulation - methods; Exploratory Behavior - physiology; Fragile X Mental Retardation Protein; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - pathology; Fragile X Syndrome - physiopathology; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Gene mutations; Genetic aspects; Health aspects; Hippocampus - pathology; Hippocampus - physiopathology; Homer Scaffolding Proteins; Immunoprecipitation; In Vitro Techniques; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Net - drug effects; Nerve Net - physiology; Neurotransmitter receptors; Patch-Clamp Techniques; Peptides - pharmacology; Physics; Physiological aspects; Protein Synthesis Inhibitors - pharmacology; Rats; Rats, Long-Evans; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - chemistry; Receptors, Metabotropic Glutamate - metabolism; Risk factors; Serine - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; TOR Serine-Threonine Kinases - metabolism; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3033

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.