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Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism

  • Biological Psychiatry - Original Article
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Abstract

Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1β1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 ± 0.40 ng/mL, ~213 ± 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.

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Abbreviations

NRG:

Neuregulin

SNP:

Single-nucleotide polymorphism

ELISA:

Enzyme-linked immunosorbent assay

LI:

Like immunoreactivity

ANOVA:

Analysis of variance

ANCOVA:

Analysis of covariance

References

  • Addington AM, Gornick MC, Shaw P, Seal J, Gogtay N, Greenstein D et al (2007) Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories. Mol Psychiatry 12:195–205

    Article  CAS  PubMed  Google Scholar 

  • Akiyama K (1999) Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 37:97–106

    Article  CAS  PubMed  Google Scholar 

  • Bakker SC, Hoogendoorn ML, Selton JP, Verduijn W, Pearson PL, Sinke RJ et al (2004) Neuregulin 1: genetic support for schizophrenia subtypes. Mol Psychiatry 9:1061–1063

    Article  CAS  PubMed  Google Scholar 

  • Bellon A (2007) New genes associated with schizophrenia in neurite formation: a review of cell culture experiments. Mol Psychiatry 12:620–629

    Article  CAS  PubMed  Google Scholar 

  • Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 20:70–73

    Article  CAS  PubMed  Google Scholar 

  • Carraway KL 3rd, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A et al (1994) The erbB3 gene product is a receptor for heregulin. J Biol Chem 269:14303–14306

    CAS  PubMed  Google Scholar 

  • Chagnon YC, Roy MA, Bureau A, Mérette C, Maziade M (2008) Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes. Schizophr Res 100:281–290

    Article  CAS  PubMed  Google Scholar 

  • Corfas G, Roy K, Buxbaum JD (2004) Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 7:575–580

    Article  CAS  PubMed  Google Scholar 

  • Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J et al (2004) Confirmation and refinement of an ‘at-risk’ haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. Mol Psychiatry 9:208–212

    Article  CAS  PubMed  Google Scholar 

  • Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30

    Article  CAS  PubMed  Google Scholar 

  • Fernandez PA, Tang DG, Cheng L, Prochiantz A, Mudge AW, Raff MC (2000) Evidence that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 28:81–90

    Article  CAS  PubMed  Google Scholar 

  • Fukui N, Muratake T, Kaneko N, Amagane H, Someya T (2006) Supportive evidence for neuregulin 1 as a susceptibility gene for schizophrenia in a Japanese population. Neurosci Lett 396:117–120

    Article  CAS  PubMed  Google Scholar 

  • Futamura T, Toyooka K, Iritani S, Niizato K, Nakamura R, Tsuchiya K et al (2002) Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. Mol Psychiatry 7:673–682

    Article  CAS  PubMed  Google Scholar 

  • Gardner M, González-Neira A, Lao O, Calafell F, Bertranpetit J, Comas D (2006) Extreme population differences across Neuregulin 1 gene, with implications for association studies. Mol Psychiatry 11:66–75

    Article  CAS  PubMed  Google Scholar 

  • Guthrie S, Lane EA, Linnoila M (1987) Monitoring of plasma drug concentrations in clinical psychopharmacology. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1323–1338

    Google Scholar 

  • Hall J, Whalley HC, Job DE, Baig BJ, Mclntosh AM, Evans KL et al (2006) A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosci 9:1477–1478

    Article  CAS  PubMed  Google Scholar 

  • Harrison PJ, Law AJ (2006) Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140

    Article  CAS  PubMed  Google Scholar 

  • Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68

    Article  CAS  PubMed  Google Scholar 

  • Harrison PJ, Heath PR, Eastwood SL, Burnet PWJ, McDonald B, Pearson RCA (1995) The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins. Neurosci Lett 200:151–154

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto R, Straub RE, Weickert CS, Hyde TM, Kleinman JE, Weinberger DR (2004) Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol Psychiatry 9:299–307

    Article  CAS  PubMed  Google Scholar 

  • Ikeda M, Takahashi N, Saito S, Aleksic B, Watanabe Y, Nunokawa A et al (2008) Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. Schizophr Res 101:1–8

    Article  PubMed  Google Scholar 

  • Inada T (2006) Pharmacologic treatment of schizophrenia: Summarized in various guidelines and algorithms. Aruta Shuppan Co, Tokyo

    Google Scholar 

  • Iwata N, Suzuki T, Ikeda M, Kitajima T, Yamanouchi Y, Inada T et al (2004) No association with the neuregulin 1 haplotype to Japanese schizophrenia. Mol Psychiatry 9:126–127

    Article  CAS  PubMed  Google Scholar 

  • Kendler KS, MacLean CJ, O’Neill FA, Burke J, Murphy B, Duke F et al (1996) Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 153:1534–1540

    CAS  PubMed  Google Scholar 

  • LaCroix-Fralish ML, Tawfik VL, Spratt KF, DeLeo JA (2006) Sex differences in lumbar spinal cord gene expression following experimental lumbar radiculopathy. J Mol Neurosci 30:283–295

    Article  CAS  PubMed  Google Scholar 

  • LaCroix-Fralish ML, Tawfik VL, Nutile-McMenemy N, Deleo JA (2008) Neuregulin 1 is a pronociceptive cytokine that is regulated by progesterone in the spinal cord: implications for sex specific pain modulation. Eur J Pain 12:94–103

    Article  CAS  PubMed  Google Scholar 

  • Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R et al (2006) Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 103:6747–6752

    Article  CAS  PubMed  Google Scholar 

  • Lawrie SM, Hall J, McIntosh AM, Cunningham-Owens DG, Johnstone EC (2008) Neuroimaging and molecular genetics of schizophrenia: pathophysiological advances and therapeutic potential. Br J Pharmacol 153:S120–S124

    Article  CAS  PubMed  Google Scholar 

  • Li T, Stefansson H, Gudfinnsson E, Cai G, Liu X, Murray RM et al (2004) Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. Mol Psychiatry 9:698–704

    CAS  PubMed  Google Scholar 

  • Li D, Collier DA, He L (2006) Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 15:1995–2002

    Article  CAS  PubMed  Google Scholar 

  • Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M et al (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:312–318

    Article  CAS  PubMed  Google Scholar 

  • Martocchia A, Sigala S, Proietti A, D’Urso R, Spano PF, Missale C et al (2002) Sex-related variations in serum nerve growth factor concentration in humans. Neuropeptides 36:391–395

    Article  CAS  PubMed  Google Scholar 

  • McIntosh AM, Moorhead TWJ, Job D, Lymer GKS, Munoz Maniega S, McKirdy J et al (2008) The effects of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry 13:1054–1059

    Article  CAS  PubMed  Google Scholar 

  • Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452

    Article  CAS  PubMed  Google Scholar 

  • Morrison-Bogorad M, Zimmerman AL, Pardue S (1995) Heat-shock 70 messenger RNA levels in human brain: correlation with agonal fever. J Neurochem 64:235–246

    CAS  PubMed  Google Scholar 

  • Munafò MR, Thiselton DL, Clark TG, Flint J (2006) Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry 11:539–546

    Article  PubMed  Google Scholar 

  • Nawa H, Carnahan J, Gall C (1995) BDNF protein measured by a novel enzyme immunoassay in normal brain and after seizure: partial disagreement with mRNA levels. Eur J Neurosci 7:1527–1535

    Article  CAS  PubMed  Google Scholar 

  • Nicodemus KK, Law AJ, Luna A, Vakkalanka R, Straub RE, Kleinman JE et al (2009) A5′ promoter region SNP in NRG1 is associated with schizophrenia risk and type III isoform expression. Mol Psychiatry 14:741–743

    Article  CAS  PubMed  Google Scholar 

  • Ozaki M, Tohyama K, Kishida H, Buonanno A, Yano R, Hashikawa T (2000) Roles of neuregulin in synaptogenesis between mossy fibers and cerebellar granule cells. J Neurosci Res 59:612–623

    Article  CAS  PubMed  Google Scholar 

  • Ozaki M, Itoh K, Miyakawa Y, Kishida H, Hashikawa T (2004) Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J Neurochem 91:176–188

    Article  CAS  PubMed  Google Scholar 

  • Petryshen TL, Middleton FA, Kirby A, Aldinger KA, Purcell S, Tahl AR et al (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10:366–374

    Article  CAS  PubMed  Google Scholar 

  • Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL et al (1995) Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. Am J Med Genet 60:252–260

    Article  CAS  PubMed  Google Scholar 

  • Schmitt A, Bertsch T, Tost H, Bergmann A, Henning U, Klimke A et al (2005) Increased serum interleukin-1beta and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication. Neuropsychiatr Dis Treat 1:171–177

    Article  CAS  PubMed  Google Scholar 

  • Sei Y, Ren-Patterson R, Li Z, Tunbridge EM, Egan MF, Kolachana BS et al (2007) Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms. Mol Psychiatry 12:946–957

    Article  CAS  PubMed  Google Scholar 

  • Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A (2001) Roles of Meltrin beta/ADAM19 in the processing of neuregulin. J Biol Chem 276:9352–9358

    Article  CAS  PubMed  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    Article  PubMed  Google Scholar 

  • Steinthorsdottir V, Stefansson H, Ghosh S, Birgisdottir B, Bjornsdottir S, Fasquel AC et al (2004) Multiple novel transcription initiation sites for NRG1. Gene 342:97–105

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K et al (2000) Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 5:293–300

    Article  CAS  PubMed  Google Scholar 

  • Tan W, Wang Y, Gold B, Chen J, Dean M, Harrison PJ et al (2007) Molecular cloning of a brain-specific, developmentally regulated neuregulin1 (NRG 1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem 282:24343–24351

    Article  CAS  PubMed  Google Scholar 

  • Tang JX, Chen WY, He G, Zhou J, Gu NF, Feng GY et al (2004) Polymorphisms within 5′ end of the neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol Psychiatry 9:11–12

    Article  CAS  PubMed  Google Scholar 

  • Thiselton DL, Webb BT, Neale BM, Ribble RC, O’Neill FA, Walsh D et al (2004) No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF). Mol Psychiatry 9:777–783

    Article  CAS  PubMed  Google Scholar 

  • Thomson PA, Christoforou A, Morris SW, Adie E, Pickard BS, Porteous DJ et al (2007) Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 12:94–104

    Article  CAS  PubMed  Google Scholar 

  • Tomita H, Vawter MP, Walsh DM, Evans SJ, Choudary PV, Li J et al (2004) Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain. Biol Psychiatry 55:346–352

    Article  CAS  PubMed  Google Scholar 

  • Toyooka K, Asama K, Watanabe Y, Muratake T, Takahashi M, Someya T et al (2002) Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Res 110:249–257

    Article  CAS  PubMed  Google Scholar 

  • Toyooka K, Watanabe Y, Iritani S, Shimizu E, Iyo M, Nakamura R et al (2003) A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients. Neurosci Res 46:299–307

    Article  CAS  PubMed  Google Scholar 

  • Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S et al (2003) Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 8:485–487

    Article  CAS  PubMed  Google Scholar 

  • Woods SW (2003) Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 64:663–667

    Article  CAS  PubMed  Google Scholar 

  • Yang JZ, Si TM, Ruan Y, Ling YS, Han YH, Wang WL et al (2003) Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 8:706–709

    Article  CAS  PubMed  Google Scholar 

  • Yokozeki T, Wakatsuki S, Hatsuzawa K, Black RA, Wada I, Sehara-Fujisawa A (2007) Meltrin beta (ADAM19) mediates ectodomain shedding of Neuregulin beta1 in the Golgi apparatus: fluorescence correlation spectroscopic observation of the dynamics of ectodomain shedding in living cells. Genes Cells 12:329–343

    Article  CAS  PubMed  Google Scholar 

  • Zhang HX, Zhao JP, Lv LX, Li WQ, Xu L, Ouyang X et al (2008) Explorative study on the expression of neuregulin-1 gene in peripheral blood of schizophrenia. Neurosci Lett 438:1–5

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank the patients and healthy volunteers for their participation. This work was supported by Health and Labor Sciences Research Grants, a grant from the Promotion of Niigata University Research Projects, Core Research for Evolutional Science and Technology from the JST Corporation, and a grant-in-aid from the Ministry of Health, Labor and Welfare, Japan.

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Authors and Affiliations

  1. Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, Niigata, 951-8585, Japan

    M. Shibuya, E. Komi, R. Wang, T. Kato, M. Sakai & H. Nawa

  2. Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Niigata, 951-8510, Japan

    M. Shibuya, Y. Watanabe, M. Sakai & T. Someya

  3. Institute for Biomedical Engineering, Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 513, Wasedatsurumaki-cho, Shinjuku-ku, Tokyo, 162-0041, Japan

    M. Ozaki

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  1. M. Shibuya
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  2. E. Komi
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  3. R. Wang
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  4. T. Kato
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  8. T. Someya
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Correspondence to H. Nawa.

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Shibuya, M., Komi, E., Wang, R. et al. Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism. J Neural Transm 117, 887–895 (2010). https://doi.org/10.1007/s00702-010-0418-3

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  • DOI: https://doi.org/10.1007/s00702-010-0418-3

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