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Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation

Acta Neuropathologica volume 130, pages 119–129 (2015)Cite this article

Abstract

Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n = 37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22 %; dimer: +54 %; p < 0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin −37 %, p < 0.001; Tamalin −30 %, p = 0.084; Preso1 −29 %, p = 0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine; there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder.

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References

  1. Beneyto M, Meador-Woodruff JH (2007) Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33:2175–2186

    PubMed  Article  Google Scholar 

  2. Catts VS, Fung SJ, Long LE, Joshi D, Vercammen A, Allen KM, Fillman SG, Rothmond DA, Sinclair D, Tiwari Y, Tsai S-Y, Weickert TW, Shannon Weickert C (2013) Rethinking schizophrenia in the context of normal neurodevelopment. Front Cell Neurosci 7:60

    PubMed Central  PubMed  Article  Google Scholar 

  3. Corti C, Crepaldi L, Mion S, Roth AL, Xuereb JH, Ferraguti F (2007) Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia. Biol Psychiatry 62:747–755

    CAS  PubMed  Article  Google Scholar 

  4. Corti C, Xuereb JH, Crepaldi L, Corsi M, Michielin F, Ferraguti F (2011) Altered levels of glutamatergic receptors and Na +/K + ATPase-α1 in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 128:7–14

    PubMed  Article  Google Scholar 

  5. El Moustaine D, Granier S, Doumazane E, Scholler P, Rahmeh R, Bron P, Mouillac B, Banères J-L, Rondard P, Pin J-P (2012) Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc Natl Acad Sci USA 109:16342–16347

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  6. Engmann O, Hortobágyi T, Pidsley R, Troakes C, Bernstein H-G, Kreutz MR, Mill J, Nikolic M, Giese KP (2011) Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain 134:2408–2421

    PubMed Central  PubMed  Article  Google Scholar 

  7. Fatemi SH, Folsom TD (2014) Existence of monomer and dimer forms of mGluR5, under reducing conditions in studies of postmortem brain in various psychiatric disorders. Schizophr Res 158:270–271

    PubMed  Article  Google Scholar 

  8. Fatemi SH, Folsom TD, Rooney RJ, Thuras PD (2013) mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway. Transl Psychiatry 3:e271.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  9. Fuxe K, Marcellino D, Rivera A, Diaz-Cabiale Z, Filip M, Gago B, Roberts DCS, Langel U, Genedani S, Ferraro L, de la Calle A, Narvaez J, Tanganelli S, Woods A, Agnati LF (2008) Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology. Brain Res Rev 58:415–452

    CAS  PubMed  Article  Google Scholar 

  10. Greenbaum D, Colangelo C, Williams K, Gerstein M (2003) Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 4:117

    PubMed Central  PubMed  Article  Google Scholar 

  11. Han M, Newell K, Zavitsanou K, Deng C, Huang XF (2008) Effects of antipsychotic medication on muscarinic M1 receptor mRNA expression in the rat brain. J Neurosci Res 86:457–464

    CAS  PubMed  Article  Google Scholar 

  12. Hu J-H, Yang L, Kammermeier PJ, Moore CG, Brakeman PR, Tu J, Yu S, Petralia RS, Li Z, Zhang P-W, Park JM, Dong X, Xiao B, Worley PF (2012) Preso1 dynamically regulates group I metabotropic glutamate receptors. Nat Neurosci 15:836–844

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  13. Javitt DC (2012) Twenty-five years of glutamate in schizophrenia: are we there yet? Schizophr Bull 38:911–913

    PubMed Central  PubMed  Article  Google Scholar 

  14. Kitano J, Kimura K, Yamazaki Y, Soda T, Shigemoto R, Nakajima Y, Nakanishi S (2002) Tamalin, a PDZ domain-containing protein, Links a Protein Complex Formation of Group 1 Metabotropic Glutamate Receptors and the Guanine Nucleotide Exchange Factor Cytohesins. J Neurosci 22:1280–1289

    CAS  PubMed  Google Scholar 

  15. Kitano J, Yamazaki Y, Kimura K, Masukado T, Nakajima Y, Nakanishi S (2003) Tamalin is a scaffold protein that interacts with multiple neuronal proteins in distinct modes of protein-protein association. J Biol Chem 278:14762–14768

    CAS  PubMed  Article  Google Scholar 

  16. Lee HW, Choi J, Shin H, Kim K, Yang J, Na M, Choi SY, Kang GB, Eom SH, Kim H et al (2008) Preso, a novel PSD-95-interacting FERM and PDZ domain protein that regulates dendritic spine morphogenesis. J Neurosci 28:14546–14556

    CAS  PubMed  Article  Google Scholar 

  17. Matosin N, Frank E, Deng C, Huang X-F, Newell KA (2013) Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. Schizophr Res 146:170–176

    PubMed  Article  Google Scholar 

  18. Matosin N, Newell KA (2013) Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia. Neurosci Biobehav Rev 37:256–268

    CAS  PubMed  Article  Google Scholar 

  19. McCullumsmith RE, Hammond JH, Shan D, Meador-Woodruff JH (2014) Postmortem brain: an underutilized substrate for studying severe mental illness. Neuropsychopharmacology 39:65–87

    PubMed Central  PubMed  Article  Google Scholar 

  20. Milligan G (2004) G protein-coupled receptor dimerization: function and ligand pharmacology. Mol Pharmacol 66:1–7

    CAS  PubMed  Article  Google Scholar 

  21. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17:1206–1227

    CAS  PubMed  Article  Google Scholar 

  22. Mochizuki R, Ishizuka Y, Yanai K, Koga Y, Fukamizu A (1999) Molecular cloning and expression of human neurochondrin-1 and -2. Biochim Biophys Acta BBA 1446:397–402

    CAS  Article  Google Scholar 

  23. Newell KA, Matosin N (2014) Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics. BMC Psychiatry 14:23

    PubMed Central  PubMed  Article  Google Scholar 

  24. Newell KA, Matosin N, Lum JS (2014) Metabotropic glutamate receptors in the pathophysiology and treatment of schizophrenia and major depression. In: Olive MF (ed) Metabotropic glutamate receptors. Molecular mechanisms, role in neurological disorders and pharmacological effects. Nova Science, New York, pp 73–106

    Google Scholar 

  25. Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC (1998) Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Mol Brain Res 56:207–217

    CAS  PubMed  Article  Google Scholar 

  26. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates: hard cover edition, 6th edn. Academic press, London

    Google Scholar 

  27. Piton A, Gauthier J, Hamdan FF, Lafrenière RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Côté M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Rivière J-B, Tarabeux J, Cossette P, Krebs M-O, Rapoport JL, Addington A, DeLisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA (2010) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16:867–880

    PubMed Central  PubMed  Article  Google Scholar 

  28. Radulovic J, Tronson NC (2012) Preso1, mGluR5 and the machinery of pain. Nat Neurosci 15:805–807

    CAS  PubMed  Article  Google Scholar 

  29. Romano C, Yang W-L, O’Malley KL (1996) Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J Biol Chem 271:28612–28616

    CAS  PubMed  Article  Google Scholar 

  30. Shinozaki K, Maruyama K, Kume H, Kuzume H, Obata K (1997) A novel brain gene, Norbin, induced by treatment of tetraethylammonium in rat hippocampal slice and accompanied with neurite-outgrowth in neuro 2a cells. Biochem Biophys Res Commun 240:766–771

    CAS  PubMed  Article  Google Scholar 

  31. Spellmann I, Rujescu D, Musil R, Mayr A, Giegling I, Genius J, Zill P, Dehning S, Opgen-Rhein M, Cerovecki A, Hartmann AM, Schäfer M, Bondy B, Müller N, Möller H-J, Riedel M (2011) Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients. J Psychiatr Res 45:234–241

    PubMed  Article  Google Scholar 

  32. Tai H-C, Besche H, Goldberg AL, Schuman EM (2010) Characterization of the brain 26S proteasome and its interacting proteins. Front Mol Neurosci 3:1–19

    Google Scholar 

  33. Tandon R, Nasrallah HA, Keshavan MS (2010) Schizophrenia, “just the facts” 5. treatment and prevention. Past, present, and future. Schizophr Res 122:1–23

    PubMed  Article  Google Scholar 

  34. Timms AE, Dorschner MO, Wechsler J, Choi KY, Kirkwood R, Girirajan S, Baker C, Eichler EE, Korvatska O, Roche KW, Horwitz MS, Tsuang DW (2013) Support for the N-methyl-d-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry Chic Ill 70:582–590

    CAS  Article  Google Scholar 

  35. Ting JT, Peça J, Feng G (2012) functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. Annu Rev Neurosci 35:49–71

    CAS  PubMed  Article  Google Scholar 

  36. Volk DW, Eggan SM, Lewis DA (2010) Alterations in metabotropic glutamate receptor 1a and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry 167:1489–1498

    PubMed Central  PubMed  Article  Google Scholar 

  37. Wang H, Nong Y, Bazan F, Greengard P, Flajolet M (2010) Norbin: a promising central nervous system regulator. Commun Integr Biol 3:487

    PubMed Central  PubMed  Article  Google Scholar 

  38. Wang H, Westin L, Nong Y, Birnbaum S, Bendor J, Brismar H, Nestler E, Aperia A, Flajolet M, Greengard P (2009) Norbin Is an endogenous regulator of metabotropic glutamate receptor 5 signaling. Science 326:1554–1557

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang X-F, Catts SV, Weickert TW (2012) Molecular evidence of N-methyl-d-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry 18(11):1185–1192

    PubMed Central  PubMed  Article  Google Scholar 

  40. Weickert CS, Sheedy D, Rothmond DA, Dedova I, Fung S, Garrick T, Wong J, Harding AJ, Sivagnanansundaram S, Hunt C, Duncan C, Sundqvist N, Tsai SY, Anand J, Draganic D, Harper C (2010) Selection of reference gene expression in a schizophrenia brain cohort. Aust N Z J Psychiatry 44:59–70

    PubMed Central  PubMed  Article  Google Scholar 

  41. Weston-Green K, Huang XF, Lian J, Deng C (2012) Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol 22:364–373

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

Postmortem brain tissues were received from the NSW Tissue Resource Centre, which is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism [NIH (NIAA) R24AA012725]. The authors wish to thank the Schizophrenia Research Laboratory for preparation of the human brain tissue samples, Jiamei Lian, Hongqin Wang, Kiefer Zhang and Meng He for their assistance with the animal antipsychotic drug treatment and brain sampling, and Shan-Yuan Tsai for assistance with the qRT-PCR analyses. Cynthia Shannon Weickert was supported by the University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute (utilizing infrastructure funding from the NSW Ministry of Health and the Macquarie Group Foundation). Cynthia Shannon Weickert is a recipient of a National Health and Medical Research Council (Australia) Senior Research Fellowship (#1021970). This study was supported by the Schizophrenia Research Institute, utilizing infrastructure funding from the NSW Ministry of Health. The animal antipsychotic drug study was supported by a National Health and Medical Research Council grant to Xu-Feng Huang (Grant ID 635231). Natalie Matosin, Jeremy S. Lum and Jessica L. Andrews are supported by Ian Scott Scholarships from Australian Rotary Health.

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Authors and Affiliations

  1. Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, NSW, 2522, Australia

    Natalie Matosin, Francesca Fernandez-Enright, Jeremy Stephen Lum, Martin Engel, Jessica Lee Andrews, Xu-Feng Huang & Kelly Anne Newell

  2. Faculty of Social Sciences, University of Wollongong, Wollongong, NSW, Australia

    Francesca Fernandez-Enright

  3. Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia

    Natalie Matosin, Francesca Fernandez-Enright, Jeremy Stephen Lum, Martin Engel, Jessica Lee Andrews, Xu-Feng Huang & Kelly Anne Newell

  4. Schizophrenia Research Institute, Sydney, NSW, Australia

    Natalie Matosin, Francesca Fernandez-Enright, Samantha Jane Fung, Jeremy Stephen Lum, Martin Engel, Jessica Lee Andrews, Xu-Feng Huang, Cynthia Shannon Weickert & Kelly Anne Newell

  5. Neuroscience Research Australia, Randwick, NSW, Australia

    Samantha Jane Fung & Cynthia Shannon Weickert

  6. School of Psychiatry, University of New South Wales, Randwick, NSW, Australia

    Samantha Jane Fung & Cynthia Shannon Weickert

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  1. Natalie Matosin
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Correspondence to Kelly Anne Newell.

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Matosin, N., Fernandez-Enright, F., Fung, S.J. et al. Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation. Acta Neuropathol 130, 119–129 (2015). https://doi.org/10.1007/s00401-015-1411-6

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  • DOI: https://doi.org/10.1007/s00401-015-1411-6

Keywords

  • Metabotropic glutamate receptor
  • GRM5
  • Immunoblot
  • Human brain
  • Schizophrenia
  • Antipsychotic