Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
| Autor: | Weirui Guo, Kimberly M. Huber, Jia Hua Hu, Jay R. Gibson, Katie A. Collins, Nien Pei Tsai, Shari G. Birnbaum, Jennifer A. Ronesi, Paul F. Worley, Seth A. Hays |
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| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
Mutation Metabotropic glutamate receptor 5 animal diseases General Neuroscience Transgene Long-term potentiation Biology medicine.disease_cause medicine.disease FMR1 Fragile X syndrome 03 medical and health sciences 0302 clinical medicine nervous system Metabotropic glutamate receptor mental disorders medicine Autism Neuroscience 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Nature Neuroscience. 15:431-440 |
| ISSN: | 1546-1726 1097-6256 |
| DOI: | 10.1038/nn.3033 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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