PT  - JOURNAL ARTICLE
AU  - Weirui Guo
AU  - Gemma Molinaro
AU  - Katie A. Collins
AU  - Seth A. Hays
AU  - Richard Paylor
AU  - Paul F. Worley
AU  - Karen K. Szumlinski
AU  - Kimberly M. Huber
TI  - Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice
AID  - 10.1523/JNEUROSCI.2921-15.2016
DP  - 2016 Feb 17
TA  - The Journal of Neuroscience
PG  - 2131--2147
VI  - 36
IP  - 7
4099  - http://www.jneurosci.org/content/36/7/2131.short
4100  - http://www.jneurosci.org/content/36/7/2131.full
SO  - J. Neurosci.2016 Feb 17; 36
AB  - 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; mGlu5R/R) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5R/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.SIGNIFICANCE STATEMENT 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.