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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.

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Figure 1: Peptide-mediated disruption of mGluR5-Homer scaffolds in WT mouse hippocampus bidirectionally regulates group 1 mGluR signaling to translation initiation and elongation.
Figure 2: mGluR5-Homer scaffolds and group 1 mGluR signaling are altered in Fmr1−/y mice and rescued by genetic deletion of H1a.
Figure 3: Altered mGluR5-Homer scaffolds in Fmr1−/y mice mediate enhanced basal translation rates and initiation complex formation.
Figure 4: Genetic deletion of Homer1a does not reverse the protein synthesis independence of mGluR-induced LTD or altered protein levels of FMRP target mRNAs.
Figure 5: Disruption of mGluR5-Homer interactions mediates prolonged neocortical UP states in Fmr1−/y mice.
Figure 6: H1a deletion reduces audiogenic seizures and corrects open field activity in the Fmr1−/y mouse.

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References

  1. Abrahams, B.S. & Geschwind, D.H. Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341–355 (2008).

    Article  CAS  Google Scholar 

  2. Bassell, G.J. & Warren, S.T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201–214 (2008).

    Article  CAS  Google Scholar 

  3. Berry-Kravis, E. Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44, 724–728 (2002).

    Article  Google Scholar 

  4. Hagerman, R. The physical and behavioral phenotype. in Fragile X Syndrome: Diagnosis, Treatment, and Research (eds. Hagerman, R. & Hagerman, P.) 3–109 (Johns Hopkins Univ. Press, Baltimore, 2002).

  5. Lüscher, C. & Huber, K.M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65, 445–459 (2010).

    Article  Google Scholar 

  6. Bear, M.F., Huber, K.M. & Warren, S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).

    Article  CAS  Google Scholar 

  7. Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

    Article  Google Scholar 

  8. Dölen, G., Carpenter, R.L., Ocain, T.D. & Bear, M.F. Mechanism-based approaches to treating fragile X. Pharmacol. Ther. 127, 78–93 (2010).

    Article  Google Scholar 

  9. Jacquemont, S. et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3, 64ra61 (2011).

    Article  Google Scholar 

  10. Giuffrida, R. et al. A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome. J. Neurosci. 25, 8908–8916 (2005).

    Article  CAS  Google Scholar 

  11. Shiraishi-Yamaguchi, Y. & Furuichi, T. The Homer family proteins. Genome Biol. 8, 206 (2007).

    Article  Google Scholar 

  12. Park, S. et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59, 70–83 (2008).

    Article  CAS  Google Scholar 

  13. Ango, F. et al. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962–965 (2001).

    Article  CAS  Google Scholar 

  14. Tu, J.C. et al. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21, 717–726 (1998).

    Article  CAS  Google Scholar 

  15. Xiao, B. et al. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21, 707–716 (1998).

    Article  CAS  Google Scholar 

  16. Mao, L. et al. The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J. Neurosci. 25, 2741–2752 (2005).

    Article  CAS  Google Scholar 

  17. Ronesi, J.A. & Huber, K.M. Metabotropic glutamate receptors and fragile X mental retardation protein: partners in translational regulation at the synapse. Sci. Signal. 1, pe6 (2008).

    Article  Google Scholar 

  18. Ronesi, J.A. & Huber, K.M. Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation. J. Neurosci. 28, 543–547 (2008).

    Article  CAS  Google Scholar 

  19. Sharma, A. et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30, 694–702 (2010).

    Article  CAS  Google Scholar 

  20. Osterweil, E.K., Krueger, D.D., Reinhold, K. & Bear, M.F. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30, 15616–15627 (2010).

    Article  CAS  Google Scholar 

  21. Hu, J.H. et al. Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron 68, 1128–1142 (2010).

    Article  CAS  Google Scholar 

  22. Gross, C. et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30, 10624–10638 (2010).

    Article  CAS  Google Scholar 

  23. Proud, C.G. Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem. J. 403, 217–234 (2007).

    Article  CAS  Google Scholar 

  24. Banko, J.L., Hou, L., Poulin, F., Sonenberg, N. & Klann, E. Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 26, 2167–2173 (2006).

    Article  CAS  Google Scholar 

  25. Herbert, T.P., Tee, A.R. & Proud, C.G. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E–BP1 at multiple sites. J. Biol. Chem. 277, 11591–11596 (2002).

    Article  CAS  Google Scholar 

  26. Kelleher, R.J. III, Govindarajan, A., Jung, H.Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

    Article  CAS  Google Scholar 

  27. Waung, M.W., Pfeiffer, B.E., Nosyreva, E.D., Ronesi, J.A. & Huber, K.M. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59, 84–97 (2008).

    Article  CAS  Google Scholar 

  28. Zalfa, F. et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327 (2003).

    Article  CAS  Google Scholar 

  29. Muddashetty, R.S. et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol. Cell 42, 673–688 (2011).

    Article  CAS  Google Scholar 

  30. Gibson, J.R., Bartley, A.F., Hays, S.A. & Huber, K.M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).

    Article  Google Scholar 

  31. Hays, S.A., Huber, K.M. & Gibson, J.R. Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J. Neurosci. 31, 14223–14234 (2011).

    Article  CAS  Google Scholar 

  32. Sanchez-Vives, M.V. & McCormick, D.A. Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat. Neurosci. 3, 1027–1034 (2000).

    Article  CAS  Google Scholar 

  33. Haider, B. & McCormick, D.A. Rapid neocortical dynamics: cellular and network mechanisms. Neuron 62, 171–189 (2009).

    Article  CAS  Google Scholar 

  34. Liu, Z.H. & Smith, C.B. Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome. Neurosci. Lett. 454, 62–66 (2009).

    Article  CAS  Google Scholar 

  35. Scheetz, A.J., Nairn, A.C. & Constantine-Paton, M. NMDA receptor-mediated control of protein synthesis at developing synapses. Nat. Neurosci. 3, 211–216 (2000).

    Article  CAS  Google Scholar 

  36. Waung, M.W. & Huber, K.M. Protein translation in synaptic plasticity: mGluR-LTD, Fragile X. Curr. Opin. Neurobiol. 19, 319–326 (2009).

    Article  CAS  Google Scholar 

  37. Rubenstein, J.L. & Merzenich, M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).

    Article  CAS  Google Scholar 

  38. Uhlhaas, P.J. & Singer, W. Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 52, 155–168 (2006).

    Article  CAS  Google Scholar 

  39. Mackiewicz, M., Paigen, B., Naidoo, N. & Pack, A.I. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate. Physiol. Genomics 33, 91–99 (2008).

    Article  CAS  Google Scholar 

  40. Brown, M.R. et al. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat. Neurosci. 13, 819–821 (2010).

    Article  CAS  Google Scholar 

  41. Thomas, A.M. et al. Genetic reduction of group 1 metabotropic glutamate receptors alters select behaviors in a mouse model for fragile X syndrome. Behav. Brain Res. 223, 310–321 (2011).

    Article  CAS  Google Scholar 

  42. Thomas, A.M., Bui, N., Perkins, J.R., Yuva-Paylor, L.A. & Paylor, R. Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. Psychopharmacology (Berl.) 219, 47–58 (2012).

    Article  CAS  Google Scholar 

  43. Darnell, J.C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

    Article  CAS  Google Scholar 

  44. Mizutani, A., Kuroda, Y., Futatsugi, A., Furuichi, T. & Mikoshiba, K. Phosphorylation of Homer3 by calcium/calmodulin-dependent kinase II regulates a coupling state of its target molecules in Purkinje cells. J. Neurosci. 28, 5369–5382 (2008).

    Article  CAS  Google Scholar 

  45. Huang, G.N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008).

    Article  CAS  Google Scholar 

  46. Orlando, L.R. et al. Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5. J. Neurochem. 110, 557–569 (2009).

    Article  CAS  Google Scholar 

  47. Bangash, M.A. et al. Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 145, 758–772 (2011).

    Article  CAS  Google Scholar 

  48. Billuart, P. et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392, 923–926 (1998).

    Article  CAS  Google Scholar 

  49. The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78, 23–33 (1994).

  50. Potschka, H. et al. Kindling-induced overexpression of Homer 1A and its functional implications for epileptogenesis. Eur. J. Neurosci. 16, 2157–2165 (2002).

    Article  CAS  Google Scholar 

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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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Contributions

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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Correspondence to Kimberly M Huber.

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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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