Psychopharmacology

, Volume 226, Issue 2, pp 201–215 | Cite as

Neuregulin-1 signalling and antipsychotic treatment

Potential therapeutic targets in a schizophrenia candidate signalling pathway
Review

Abstract

Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)–ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1–ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1–ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1–ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1–ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1–ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1–ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.

Keywords

Schizophrenia Neuregulin-1 ErbB4 receptor Antipsychotic Glutamatergic GABA Dopaminergic Drug target 

Notes

Acknowledgements

This study was supported by a University of Wollongong URC grant and an NHMRC project grant (APP1008473) to C. Deng, and the Schizophrenia Research Institute, Australia, utilising infrastructure funding from NSW Health. We would like to thank Dr Katrina Green for her critical reading of this manuscript.

Conflict of interest

The authors have no conflicts of interest to disclose.

References

  1. Abe Y, Namba H, Zheng Y, Nawa H (2009) In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: implication of ErbB receptors for dopaminergic neurons. Neuroscience 161:95–110PubMedCrossRefGoogle Scholar
  2. Anton ES, Marchionni MA, Lee KF, Rakic P (1997) Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 124:3501–3510PubMedGoogle Scholar
  3. Austin J (2005) Schizophrenia: an update and review. J Genet Couns 14:329–340PubMedCrossRefGoogle Scholar
  4. Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848–870PubMedCrossRefGoogle Scholar
  5. Bao J, Wolpowitz D, Role LW, Talmage DA (2003) Back signaling by the Nrg-1 intracellular domain. J Cell Biol 161:1133–1141PubMedCrossRefGoogle Scholar
  6. Barakat A, Dean B, Scarr E, Evin G (2010) Decreased neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. Schizophr Res 124:200–207PubMedCrossRefGoogle Scholar
  7. Bare DJ, Becker-Catania SG, DeVries GH (2011) Differential localization of neuregulin-1 type III in the central and peripheral nervous system. Brain Res 1369:10–20PubMedCrossRefGoogle Scholar
  8. Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K et al (2009) Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci U S A 106:4507–4512PubMedCrossRefGoogle Scholar
  9. Benes FM (2009) Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate, or something else? Biol Psychiatry 65:1003–1005PubMedCrossRefGoogle Scholar
  10. Bermingham-McDonogh O, McCabe KL, Reh TA (1996) Effects of GGF/neuregulins on neuronal survival and neurite outgrowth correlate with erbB2/neu expression in developing rat retina. Development 122:1427–1438PubMedGoogle Scholar
  11. Bernstein H-G, Lendeckel U, Bertram I, Bukowska A, Kanakis D, Dobrowolny H et al (2006) Localization of neuregulin-1β (heregulin-β) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain. Brain Res Bull 69:546–559PubMedCrossRefGoogle Scholar
  12. Bertram I, Bernstein HG, Lendeckel U, Bukowska A, Dobrowolny H, Keilhoff G et al (2007) Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. Ann N Y Acad Sci 1096:147–156PubMedCrossRefGoogle Scholar
  13. Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H et al (2007) Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/− knock-outs compared with wild-type mice. J Neurosci 27:4519–4529PubMedCrossRefGoogle Scholar
  14. Bublil EM, Yarden Y (2007) The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 19:124–134PubMedCrossRefGoogle Scholar
  15. Buonanno A (2010) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. Brain Res Bull 83:122–131PubMedCrossRefGoogle Scholar
  16. Calaora V, Rogister B, Bismuth K, Murray K, Brandt H, Leprince P et al (2001) Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro. J Neurosci 21:4740–4751PubMedGoogle Scholar
  17. Canoll PD, Musacchio JM, Hardy R, Reynolds R, Marchionni MA, Salzer JL (1996) GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 17:229–243PubMedCrossRefGoogle Scholar
  18. Carlsson T, Schindler FR, Hollerhage M, Depboylu C, Arias-Carrion O, Schnurrbusch S et al (2011) Systemic administration of neuregulin-1beta1 protects dopaminergic neurons in a mouse model of Parkinson's disease. J Neurochem 117:1066–1074PubMedCrossRefGoogle Scholar
  19. Chana G, Lucero G, Salaria S, Lozach J, Du P, Woelk C, Everall I (2009) Upregulation of NRG-1 and VAMP-1 in human brain aggregates exposed to clozapine. Schizophr Res 113:273–276PubMedCrossRefGoogle Scholar
  20. Chen B-S, Braud S, Badger JD, Isaac JTR, Roche KW (2006) Regulation of NR1/NR2C N-methyl-d-aspartate (NMDA) receptors by phosphorylation. J Biol Chem 281:16583–16590PubMedCrossRefGoogle Scholar
  21. Chen Y-J, Zhang M, Yin D-M, Wen L, Ting A, Wang P et al (2010a) ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci U S A 107:21818–21823PubMedCrossRefGoogle Scholar
  22. Chen Y-JJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S, Lewandowski N et al (2008) Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci 28:6872–6883PubMedCrossRefGoogle Scholar
  23. Chen Y, Hancock ML, Role LW, Talmage DA (2010b) Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons. J Neurosci 30:9199–9208PubMedGoogle Scholar
  24. Chesworth R, Downey L, Logge W, Killcross S, Karl T (2012) Cognition in female transmembrane domain neuregulin 1 mutant mice. Behav Brain Res 226:218–223PubMedCrossRefGoogle Scholar
  25. Chong VZ, Thompson M, Beltaifa S, Webster MJ, Law AJ, Weickert CS (2008) Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. Schizophr Res 100:270–280PubMedCrossRefGoogle Scholar
  26. Cooper MA, Koleske AJ (2011) ErbB4 localization to interneurons: clearer insights into schizophrenia pathology. Biol Psychiatry 70:602–603PubMedCrossRefGoogle Scholar
  27. Correll CU (2010) From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. European Psychiatry 25. Supplement 2:S12–S21Google Scholar
  28. Cousins SL, Kenny AV, Stephenson FA (2009) Delineation of additional PSD-95 binding domains within NMDA receptor NR2 subunits reveals differences between NR2A/PSD-95 and NR2B/PSD-95 association. Neuroscience 158:89–95PubMedCrossRefGoogle Scholar
  29. Deakin IH, Law AJ, Oliver PL, Schwab MH, Nave KA, Harrison PJ, Bannerman DM (2009) Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport 20:1523–1528PubMedCrossRefGoogle Scholar
  30. Dejaegere T, Serneels L, Schäfer MK, Van Biervliet J, Horré K, Depboylu C et al (2008) Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci U S A 105:9775–9780PubMedCrossRefGoogle Scholar
  31. Deng C, Huang X-F (2006) Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia. Exp Brain Res 168:587–590PubMedCrossRefGoogle Scholar
  32. Deng C, Weston-Green K, Huang X-F (2010) The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog in Neuro-Psychopharmacology and BiolPsychiatry 34:1–4CrossRefGoogle Scholar
  33. Desbonnet L, Waddington JL, O'Tuathaigh CMP (2009) Mutant models for genes associated with schizophrenia. Biochem Soc Trans 37:308–312PubMedCrossRefGoogle Scholar
  34. Duffy L, Cappas E, Lai D, Boucher AA, Karl T (2010) Cognition in transmembrane domain neuregulin 1 mutant mice. Neuroscience 170:800–807PubMedCrossRefGoogle Scholar
  35. Duffy L, Cappas E, Scimone A, Schofield PR, Karl T (2008) Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1. Behav Neurosci 122:748–759PubMedCrossRefGoogle Scholar
  36. Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30PubMedCrossRefGoogle Scholar
  37. Fatemi SH, Folsom TD (2009): The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophrenia BulletinGoogle Scholar
  38. Fazzari P, Paternain AV, Valiente M, Pla R, Lujan R, Lloyd K et al (2010) Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464:1376–1380PubMedCrossRefGoogle Scholar
  39. Gao R, Zhang J, Cheng L, Wu X, Dong W, Yang X et al (2010) A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol 55:1907–1914PubMedCrossRefGoogle Scholar
  40. Garcia-Barcelo M-M, Miao X, Tang CS, So H-C, Tang W, Leon TYY et al (2011) No NRG1 V266L in Chinese patients with schizophrenia. Psychiatr Genet 21:47–49PubMedCrossRefGoogle Scholar
  41. Garcia RAG, Vasudevan K, Buonanno A (2000) The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc Natl Acad Sci 97:3596–3601PubMedCrossRefGoogle Scholar
  42. Geddes AE, Huang X-F, Newell KA (2011) Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:896–904PubMedCrossRefGoogle Scholar
  43. Gerecke KM, Wyss JM, Carroll SL (2004) Neuregulin-1beta induces neurite extension and arborization in cultured hippocampal neurons. Mol Cell Neurosci 27:379–393PubMedCrossRefGoogle Scholar
  44. Gerlai R, Pisacane P, Erickson S (2000) Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav Brain Res 109:219–227PubMedCrossRefGoogle Scholar
  45. Greenwood TA, Light GA, Swerdlow NR, Radant AD, Braff DL (2012) Association analysis of 94 candidate genes and schizophrenia-related endophenotypes. PLoS ONE [Electronic Resource] 7:e29630CrossRefGoogle Scholar
  46. Gu Z, Jiang Q, Fu A, Ip N, Yan Z (2005) Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J Neurosci 25:4974–4984PubMedCrossRefGoogle Scholar
  47. Hahn C-G (2011) A Src link in schizophrenia. Nat Med 17:425–427PubMedCrossRefGoogle Scholar
  48. Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH et al (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12:824–828PubMedCrossRefGoogle Scholar
  49. Hall J, Whalley HC, Job DE, Baig BJ, McIntosh AM, Evans KL et al (2006) A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosci 9:1477–1478PubMedCrossRefGoogle Scholar
  50. Hashimoto R, Straub R, Weickert C, Hyde T, Kleinman J, Weinberger D (2004) Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Molecular Psychiatry 9:299–307PubMedCrossRefGoogle Scholar
  51. Hashimoto R, Tankou S, Takeda M, Sawa A (2007) Postsynaptic density: a key convergent site for schizophrenia susceptibility factors and possible target for drug development. Drugs of Today (Barc) 43:645–654CrossRefGoogle Scholar
  52. Hong LE, Wonodi I, Stine OC, Mitchell BD, Thaker GK (2008) Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition. Biol Psychiatry 63:17–23PubMedCrossRefGoogle Scholar
  53. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9:1520–1525PubMedCrossRefGoogle Scholar
  54. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS et al (2000) Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26:443–455PubMedCrossRefGoogle Scholar
  55. 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 101:1–8PubMedCrossRefGoogle Scholar
  56. Ingason A, Soeby K, Timm S, Wang AG, Jakobsen KD, Fink-Jensen A et al (2006) No significant association of the 5′ end of neuregulin 1 and schizophrenia in a large Danish sample. Schizophr Res 83:1–5PubMedCrossRefGoogle Scholar
  57. Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A (2009) Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci 32:485–495PubMedCrossRefGoogle Scholar
  58. Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF et al (2011) Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail 13:83–92PubMedCrossRefGoogle Scholar
  59. Jones JT, Akita RW, Sliwkowski MX (1999) Binding specificities and affinities of egf domains for ErbB receptors. FEBS Lett 447:227–231PubMedCrossRefGoogle Scholar
  60. Jonsson EG, Saetre P, Vares M, Andreou D, Larsson K, Timm S et al (2009) DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 59:142–150PubMedCrossRefGoogle Scholar
  61. Junttila TT, Sundvall M, Maatta JA, Elenius K (2000) Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends in cardiovas med 10:304–310CrossRefGoogle Scholar
  62. Kainulainen V, Sundvall M, Maatta JA, Santiestevan E, Klagsbrun M, Elenius K (2000) A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem 275:8641–8649PubMedCrossRefGoogle Scholar
  63. Kampman O, Anttila S, Illi A, Saarela M, Rontu R, Mattila KM et al (2004) Neuregulin genotype and medication response in Finnish patients with schizophrenia. Neuroreport 15:2517–2520PubMedCrossRefGoogle Scholar
  64. Kanazawa T, Glatt SJ, Tsutsumi A, Kikuyama H, Koh J, Yoneda H, Tsuang MT (2007) Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case–control study. Am J Med Genet B Neuropsychiatr Genet 144B:113–116PubMedCrossRefGoogle Scholar
  65. Kang C, Yang X, Xu X, Liu H, Su P, Yang J (2012) Association study of neuregulin 1 gene polymorphisms with auditory P300 in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 159B:422–428PubMedCrossRefGoogle Scholar
  66. Kantrowitz JT, Javitt DC (2010) N-Methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 83:108–121PubMedCrossRefGoogle Scholar
  67. Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE et al (2010) Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 31:381–390PubMedCrossRefGoogle Scholar
  68. Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR (2007) Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav 6:677–687PubMedCrossRefGoogle Scholar
  69. Kastin AJ, Akerstrom V, Pan W (2004) Neuregulin-1-β1 enters brain and spinal cord by receptor-mediated transport. J Neurochem 88:965–970PubMedCrossRefGoogle Scholar
  70. Kato T, Abe Y, Sotoyama H, Kakita A, Kominami R, Hirokawa S et al (2011) Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. Mol Psychiatry 16:307–320PubMedCrossRefGoogle Scholar
  71. Kato T, Kasai A, Mizuno M, Fengyi L, Shintani N, Maeda S et al (2010) Phenotypic characterization of transgenic mice overexpressing neuregulin-1. PLoS ONE [Electron Res] 5:e14185CrossRefGoogle Scholar
  72. Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26:1604–1615PubMedCrossRefGoogle Scholar
  73. Kiss I, Kelemen O, Kéri S (2012) Decreased peripheral expression of neuregulin 1 in high-risk individuals who later converted to psychosis. Schizophr Res 135:198–199PubMedCrossRefGoogle Scholar
  74. Konrad A, Vucurevic G, Musso F, Stoeter P, Dahmen N, Winterer G (2009) ErbB4 genotype predicts left frontotemporal structural connectivity in human brain. Neuropsychopharmacology 34:641–650PubMedCrossRefGoogle Scholar
  75. Krivosheya D, Tapia L, Levinson JN, Huang K, Kang Y, Hines R et al (2008) ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. J Biol Chem 283:32944–32956PubMedCrossRefGoogle Scholar
  76. Kwon OB, Longart M, Vullhorst D, Hoffman DA, Buonanno A (2005) Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci 25:9378–9383PubMedCrossRefGoogle Scholar
  77. Kwon OB, Paredes D, Gonzalez CM, Neddens J, Hernandez L, Vullhorst D, Buonanno A (2008) Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A 105:15587–15592PubMedCrossRefGoogle Scholar
  78. Lang UE, Puls I, Muller DJ, Strutz-Seebohm N, Gallinat J (2007) Molecular mechanisms of schizophrenia. Cell Physiol Biochem 20:687–702PubMedCrossRefGoogle Scholar
  79. Law AJ, Kleinman JE, Weinberger DR, Weickert CS (2007) Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet 16:129–141PubMedCrossRefGoogle Scholar
  80. 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. Nat Acadof Sci of the USA 103:6747–6752CrossRefGoogle Scholar
  81. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41PubMedCrossRefGoogle Scholar
  82. Lewis DA, Gonzalez-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022PubMedCrossRefGoogle Scholar
  83. Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of {gamma}-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376PubMedCrossRefGoogle Scholar
  84. Li D, Collier DA, He L (2006) Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 15:1995–2002PubMedCrossRefGoogle Scholar
  85. Li D, Feng G, He L (2009a) Case–control study of association between the functional candidate gene ERBB3 and schizophrenia in Caucasian population. World J of biol psychiatry: the official J of the World Federation of Societies of Biol Psychiatry 10:595–598CrossRefGoogle Scholar
  86. Li D, He G, Xu Y, Duan Y, Gu N, Li X et al (2009b) Schizophrenia is not associated with the ERBB3 gene in a Han Chinese population sample: results from case–control and family-based studies. Genet Mol Biol 32:729–730PubMedCrossRefGoogle Scholar
  87. Lipska BK, Lerman DN, Khaing ZZ, Weinberger DR (2003) The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain. Eur J Neurosci 18:3097–3104PubMedCrossRefGoogle Scholar
  88. Liu C-M, Hwu H-G, Fann CSJ, Lin C-Y, Liu Y-L, Ou-Yang W-C, Lee SFC (2005) Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. Am J Med Genetics Part B: Neuropsychiatric Genet 134B:79–83CrossRefGoogle Scholar
  89. Liu X, Bates R, Yin D-M, Shen C, Wang F, Su N et al (2011) Specific regulation of NRG1 isoform expression by neuronal activity. J Neurosci 31:8491–8501PubMedCrossRefGoogle Scholar
  90. Long LE, Chesworth R, Arnold JC, Karl T (2010a) A follow-up study: acute behavioural effects of Delta(9)-THC in female heterozygous neuregulin 1 transmembrane domain mutant mice. Psychopharmacology (Berl) 211:277–289CrossRefGoogle Scholar
  91. Long LE, Chesworth R, Huang X-F, McGregor IS, Arnold JC, Karl T (2010b) A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol 13:861–876PubMedCrossRefGoogle Scholar
  92. Lopez-Bendito G, Cautinat A, Sanchez JA, Bielle F, Flames N, Garratt AN et al (2006) Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 125:127–142PubMedCrossRefGoogle Scholar
  93. Lu C-L, Wang Y-C, Chen J-Y, Lai IC, Liou Y-J (2010) Support for the involvement of the ERBB4 gene in schizophrenia: a genetic association analysis. Neurosci Lett 481:120–125PubMedCrossRefGoogle Scholar
  94. Mahar I, Tan S, Davoli MA, Dominguez-Lopez S, Qiang C, Rachalski A et al (2011) ubchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PLoS ONE [Elec Res] 6:e26610CrossRefGoogle Scholar
  95. Mathews M, David JM (2007) Atypical antipsychotics: new drugs, new challenges. Cleveland Clinic J Med 74:579–606CrossRefGoogle Scholar
  96. Mei L, Xiong W-C (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev 9:437–452Google Scholar
  97. Meltzer HY, Massey BW (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11:59–67PubMedCrossRefGoogle Scholar
  98. Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C et al (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Sci (New York, NY) 304:700–703CrossRefGoogle Scholar
  99. Moghaddam B (2003) Bringing order to the glutamate chaos in schizophrenia. Neuron 40:881–884PubMedCrossRefGoogle Scholar
  100. Montero JC, Rodriguez-Barrueco R, Yuste L, Juanes PP, Borges J, Esparis-Ogando A, Pandiella A (2007) The extracellular linker of pro-neuregulin-{alpha}2c is required for efficient sorting and juxtacrine function. Mol Biol Cell 18:380–393PubMedCrossRefGoogle Scholar
  101. Munafo MR, Thiselton DL, Clark TG, Flint J (2006) Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry 11:539–546PubMedCrossRefGoogle Scholar
  102. Murray CJ, Lopez AD (1996) The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Harvard School of Public Health, Cambridge, MAGoogle Scholar
  103. Nason MW Jr, Adhikari A, Bozinoski M, Gordon JA, Role LW (2011) Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice. Neuropsychopharmacology 36:488–496PubMedCrossRefGoogle Scholar
  104. Nave KA, Salzer JL (2006) Axonal regulation of myelination by neuregulin 1. Curr Opin Neurobiol 16:492–500PubMedCrossRefGoogle Scholar
  105. Neddens J, Buonanno A (2010) Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus 20:724–744PubMedGoogle Scholar
  106. Neddens J, Fish KN, Tricoire L, Vullhorst D, Shamir A, Chung W et al (2011) Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biol Psychiatry 70:636–645PubMedCrossRefGoogle Scholar
  107. Neddens J, Vullhorst D, Buonanno A (2009) Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity. Communicative and Integr Biol 2:261–264CrossRefGoogle Scholar
  108. Nicodemus KK, Law AJ, Radulescu E, Luna A, Kolachana B, Vakkalanka R et al (2010) Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. Arch Gen Psychiatry 67:991–1001PubMedCrossRefGoogle Scholar
  109. Nicodemus KK, Luna A, Vakkalanka R, Goldberg T, Egan M, Straub RE, Weinberger DR (2006) Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Mol Psychiatry 11:1062–1065PubMedCrossRefGoogle Scholar
  110. O'Tuathaigh CM, Babovic D, O'Sullivan GJ, Clifford JJ, Tighe O, Croke DT et al (2007) Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1. Neuroscience 147:18–27PubMedCrossRefGoogle Scholar
  111. O'Tuathaigh CM, O'Sullivan GJ, Kinsella A, Harvey RP, Tighe O, Croke DT, Waddington JL (2006) Sexually dimorphic changes in the exploratory and habituation profiles of heterozygous neuregulin-1 knockout mice. Neuroreport 17:79–83PubMedCrossRefGoogle Scholar
  112. O'Tuathaigh CMP, Harte M, O'Leary C, O'Sullivan GJ, Blau C, Lai D et al (2010) Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice. Eur J Neurosci 31:349–358PubMedCrossRefGoogle Scholar
  113. O'Tuathaigh CMP, O'Connor A-M, O'Sullivan GJ, Lai D, Harvey R, Croke DT, Waddington JL (2008) Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous 'knockout' of the schizophrenia risk gene neuregulin-1. Prog Neuropsychopharmacol Biol Psychiatry 32:462–466PubMedCrossRefGoogle Scholar
  114. Pan B, Huang X-F, Deng C (2011) Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:924–930PubMedCrossRefGoogle Scholar
  115. Parlapani E, Schmitt A, Wirths O, Bauer M, Sommer C, Rueb U et al (2010) Gene expression of neuregulin-1 isoforms in different brain regions of elderly schizophrenia patients. World J Biol Psychiatry 11:243–250PubMedCrossRefGoogle Scholar
  116. 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):328CrossRefGoogle Scholar
  117. Pinkas-Kramarski R, Shelly M, Glathe S, Ratzkin BJ, Yarden Y (1996) Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations. J Biol Chem 271:19029–19032PubMedCrossRefGoogle Scholar
  118. Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, Salter MW (2011) Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med 17:470–478PubMedCrossRefGoogle Scholar
  119. Rethelyi JM, Bakker SC, Polgar P, Czobor P, Strengman E, Pasztor PI et al (2010) Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample. Am J Med Genet B Neuropsychiatr Genet 153B:792–801PubMedGoogle Scholar
  120. Rico B, Marin O (2011) Neuregulin signaling, cortical circuitry development and schizophrenia. Curr Opin Genet Dev 21:262–270PubMedCrossRefGoogle Scholar
  121. Rieff HI, Corfas G (2006) ErbB receptor signalling regulates dendrite formation in mouse cerebellar granule cells in vivo. Eur J Neurosci 23:2225–2229PubMedCrossRefGoogle Scholar
  122. Rieff HI, Raetzman LT, Sapp DW, Yeh HH, Siegel RE, Corfas G (1999) Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J Neurosci 19:10757–10766PubMedGoogle Scholar
  123. Rimer M, Barrett DW, Maldonado MA, Vock VM, Gonzalez-Lima F (2005) Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition. Neuroreport 16:271–275PubMedCrossRefGoogle Scholar
  124. Rio C, Rieff HI, Qi P, Khurana TS, Corfas G (1997) Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 19:39–50PubMedCrossRefGoogle Scholar
  125. Role LW, Talmage DA (2007) Neurobiology: new order for thought disorders. Nature 448:263–265PubMedCrossRefGoogle Scholar
  126. Rösler TW, Depboylu C, Arias-Carrión O, Wozny W, Carlsson T, Höllerhage M et al (2011) Biodistribution and brain permeability of the extracellular domain of neuregulin-1-β1. Neuropharmacology 61:1413–1418PubMedCrossRefGoogle Scholar
  127. Ross CA, Margolis RL (2009) Schizophrenia: a point of disruption. Nature 458:976–977PubMedCrossRefGoogle Scholar
  128. Roussos P, Giakoumaki SG, Adamaki E, Bitsios P (2011) The influence of schizophrenia-related neuregulin-1 polymorphisms on sensorimotor gating in healthy males. Biol Psychiatry 69:479–486PubMedCrossRefGoogle Scholar
  129. Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM et al (2007) Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci U S A 104:8131–8136PubMedCrossRefGoogle Scholar
  130. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC (2008) Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA 105:5585–5590PubMedCrossRefGoogle Scholar
  131. Schmitt A, Koschel J, Zink M, Bauer M, Sommer C, Frank J et al (2010) Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. Eur Arch of Psychiatry and Clin Neurosci 260:101–111CrossRefGoogle Scholar
  132. Schmucker J, Ader M, Brockschnieder D, Brodarac A, Bartsch U, Riethmacher D (2003) erbB3 is dispensable for oligodendrocyte development in vitro and in vivo. Glia 44:67–75PubMedCrossRefGoogle Scholar
  133. Shamir A, Kwon O-B, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, Buonanno A (2012) The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders. J Neurosci 32:2988–2997PubMedCrossRefGoogle Scholar
  134. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA (2010) ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A 107:7692–7697PubMedCrossRefGoogle Scholar
  135. Shibuya M, Komi E, Wang R, Kato T, Watanabe Y, Sakai M et al (2010) Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism. J Neural Transm Suppl 117:887–895CrossRefGoogle Scholar
  136. Shiota S, Tochigi M, Shimada H, Ohashi J, Kasai K, Kato N et al (2008) Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population. J Hum Genet 53:929–935PubMedCrossRefGoogle Scholar
  137. Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R (2006) The involvement of ErbB4 with schizophrenia: association and expression studies. Am J Med Genet B Neuropsychiatr Genet 141B:142–148PubMedCrossRefGoogle Scholar
  138. Squassina A, Piccardi P, Del Zompo M, Rossi A, Vita A, Pini S et al (2010) NRG1 and BDNF genes in schizophrenia: an association study in an Italian case–control sample. Psychiatry Res 176:82–84PubMedCrossRefGoogle Scholar
  139. Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 72:83–87PubMedCrossRefGoogle Scholar
  140. Stefansson H, Sigurdsson E, Steinthorsdottir V (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:887–892CrossRefGoogle Scholar
  141. Taveggia C, Zanazzi G, Petrylak A, Yano H, Rosenbluth J, Einheber S et al (2005) Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47:681–694PubMedCrossRefGoogle Scholar
  142. Taylor SB, Markham JA, Taylor AR, Kanaskie BZ, Koenig JI (2011) Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats. Behav Brain Res 224:223–232PubMedCrossRefGoogle Scholar
  143. Thompson M, Lauderdale S, Webster MJ, Chong VZ, McClintock B, Saunders R, Weickert CS (2007) Widespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain. Brain Res 1139:95–109PubMedCrossRefGoogle Scholar
  144. Ting AK, Chen Y, Wen L, Yin D-M, Shen C, Tao Y et al (2011) Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci 31:15–25PubMedCrossRefGoogle Scholar
  145. Tseng KY, Chambers RA, Lipska BK (2009) The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res 204:295–305PubMedCrossRefGoogle Scholar
  146. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S et al (1994) ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 269:25226–25233PubMedGoogle Scholar
  147. van den Buuse M, Wischhof L, Lee RX, Martin S, Karl T (2009) Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation. Int J Neuropsychopharmacol 29:1–11Google Scholar
  148. Vohora D (2007) Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia. Curr Opin Investig Drugs 8:531–538PubMedGoogle Scholar
  149. Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, Buonanno A (2009) Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci 29:12255–12264PubMedCrossRefGoogle Scholar
  150. Wakatsuki S, Kurisaki T, Sehara-Fujisawa A (2004) Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin β/ADAM19. J Neurochem 89:119–123PubMedCrossRefGoogle Scholar
  151. Wang X-D, Su Y-A, Guo C-M, Yang Y, Si T-M (2008) Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol 11:553–561PubMedGoogle Scholar
  152. Wen D, Suggs SV, Karunagaran D, Liu N, Cupples RL, Luo Y et al (1994) Structural and functional aspects of the multiplicity of Neu differentiation factors. Mol Cell Biol 14:1909–1919PubMedGoogle Scholar
  153. Wen L, Lu Y-S, Zhu X-H, Li X-M, Woo R-S, Chen Y-J et al (2010) Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci U S A 107:1211–1216PubMedCrossRefGoogle Scholar
  154. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A et al (2006) Control of peripheral nerve myelination by the {beta}-secretase BACE1. Science (New York, NY) 314:664–666CrossRefGoogle Scholar
  155. Williams N, Preece A, Spurlock G, Norton N, Williams H, Zammit S (2003) Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Molecular Psychiatry 8:485–487PubMedCrossRefGoogle Scholar
  156. Woo R-S, Li X-M, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J et al (2007) Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54:599–610PubMedCrossRefGoogle Scholar
  157. Woo T-UW, Kim AM, Viscidi E (2008) Disease-specific alterations in glutamatergic neurotransmission on inhibitory interneurons in the prefrontal cortex in schizophrenia. Brain Res 1218:267–277PubMedCrossRefGoogle Scholar
  158. Woo T-UW, Walsh JP, Benes FM (2004) Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-d-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61:649–657PubMedCrossRefGoogle Scholar
  159. Xu Z, Croslan DR, Harris AE, Ford GD, Ford BD (2006) Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke.[Erratum appears in J Cereb Blood Flow Metab. 2008 Sep;28(9):1643 Note: Dosage error in article text]. J Cereb Blood Flow Metab 26:527–535PubMedCrossRefGoogle Scholar
  160. Xu Z, Jiang J, Ford G, Ford BD (2004) Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun 322:440–446PubMedCrossRefGoogle Scholar
  161. Yamamori H, Hashimoto R, Verrall L, Yasuda Y, Ohi K, Fukumoto M et al (2011) Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia. J Hum Genet 56:478–483PubMedCrossRefGoogle Scholar
  162. Yang J, Si T, Ruan Y, Ling Y, Han Y, Wany X (2003) Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 8:706–709PubMedCrossRefGoogle Scholar
  163. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137PubMedCrossRefGoogle Scholar
  164. Yau HJ, Wang HF, Lai C, Liu FC (2003) Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb Cortex 13:252–264PubMedCrossRefGoogle Scholar
  165. Yokley JL, Prasad KM, Chowdari KV, Talkowski ME, Wood J, Gur RC et al (2012) Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families. Psychiatr Genet 22:70–81PubMedCrossRefGoogle Scholar
  166. Yokozeki T, Wakatsuki S, Hatsuzawa K, Black RA, Wada I, Sehara-Fujisawa A (2007) Meltrin β (ADAM19) mediates ectodomain shedding of Neuregulin β1 in the Golgi apparatus: fluorescence correlation spectroscopic observation of the dynamics of ectodomain shedding in living cells. Genes to Cells 12:329–343PubMedCrossRefGoogle Scholar
  167. Yu XM, Askalan R, Keil GJ 2nd, Salter MW (1997) NMDA channel regulation by channel-associated protein tyrosine kinase Src. Sci (New York, NY) 275:674–678CrossRefGoogle Scholar
  168. Yurek DM, Zhang L, Fletcher-Turner A, Seroogy KB (2004) Supranigral injection of neuregulin1-β induces striatal dopamine overflow. Brain Res 1028:116–119PubMedCrossRefGoogle Scholar
  169. Zhang H-X, Li W-Q, Zhang H-S, Zhang Y, Zhao J-P, Lv L-X, Yang G (2011) Expressional changes of neuregulin-1 gene mRNA in peripheral blood from schizophrenia patients. Chung Hua I Hsueh I Chuan Hsueh Tsa Chih 28:620–624Google Scholar
  170. Zhang H-X, Zhao J-P, Lv L-X, Li W-Q, Xu L, Ouyang X et al (2008) Explorative study on the expression of neuregulin-1 gene in peripheral blood of schizophrenia. Neurosci Lett 438:1–5PubMedCrossRefGoogle Scholar
  171. Zheng Y, Watakabe A, Takada M, Kakita A, Namba H, Takahashi H et al (2009) Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans. Prog Neuropsychopharmacol Biol Psychiatry 33:701–706PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Chao Deng
    • 1
    • 2
    • 3
    • 4
  • Bo Pan
    • 1
    • 2
  • Martin Engel
    • 2
    • 3
  • Xu-Feng Huang
    • 2
    • 3
  1. 1.Antipsychotic Research Laboratory, Illawarra Health and Medical Research InstituteUniversity of WollongongWollongongAustralia
  2. 2.Centre for Translational Neuroscience, School of Health Sciences, and Illawarra Health and Medical Research InstituteUniversity of WollongongWollongongAustralia
  3. 3.Schizophrenia Research InstituteDarlinghurstAustralia
  4. 4.Illawarra Health and Medical Research InstituteUniversity of WollongongWollongongAustralia

Personalised recommendations