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.
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Acknowledgements
We would like to thank L. Ormazabal and N. Cabalo for technical assistance. This research was supported by the grants from the US National Institutes of Health NS045711, HD052731 (K.M.H.), HD056370 (J.R.G.), GM008203 (S.A.H.), Autism Speaks (K.M.H.), FRAXA Research Foundation and The Hartwell Foundation (J.A.R.).
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J.A.R. designed, performed and analyzed experiments included in Figures 2, 3, 4 and 6, Supplementary Figures 1 and 2 and Supplementary Tables 1 and 2 and wrote a first draft of the manuscript. K.A.C. performed and analyzed experiments in Figures 1 and 3, Supplementary Figures 2–4 and Supplementary Table 1. S.A.H. performed and analyzed experiments in Figures 5 and 6. N.-P.T. performed and analyzed coimmunoprecipitation experiments for Figures 2 and 3 and Supplementary Figure 2. W.G. performed and analyzed experiments for Figures 1, 2, 3, 4. S.G.B. provided intellectual input on the behavioral experiments and designed and performed experiments in Figure 6 and Supplementary Figure 5. J.-H.H. and P.F.W. provided intellectual input and generated and provided the H1a−/− mice. J.R.G. contributed intellectually to the overall project and in particular to the UP state experiments (Fig. 5). J.R.G. trained and supervised S.A.H., designed experiments for Figure 5, contributed funding and edited the manuscript. K.M.H. supervised the overall project, designed experiments, contributed funding, edited figures and wrote the final version of the manuscript.
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Ronesi, J., Collins, K., Hays, S. et al. Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15, 431–440 (2012). https://doi.org/10.1038/nn.3033
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DOI: https://doi.org/10.1038/nn.3033
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