Perspective | Published:

Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia

Nature Neuroscience volume 7, pages 575580 (2004) | Download Citation

Subjects

Abstract

Schizophrenia is a devastating psychiatric disease that affects 0.5–1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of erbB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002).

  2. 2.

    & Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334 (2000).

  3. 3.

    , & Genes, environment and schizophrenia. Br. J. Psychiatry Suppl. 40, s18–24 (2001).

  4. 4.

    Linkage analysis in psychiatric disorders: the emerging picture. Annu. Rev. Genomics Hum. Genet. 3, 371–413 (2002).

  5. 5.

    & Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 287–296 (2001).

  6. 6.

    , , , & Differential expression of ARIA isoforms in the rat brain. Neuron 14, 103–115 (1995).

  7. 7.

    , , , & ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72, 801–815 (1993).

  8. 8.

    et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362, 312–318 (1993).

  9. 9.

    , , , & Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 19, 39–50 (1997).

  10. 10.

    , , & Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 124, 3501–3510 (1997).

  11. 11.

    , , & Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat. Exp. Neurol. 159, 494–503 (1999).

  12. 12.

    , , & 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, 252–264 (2003).

  13. 13.

    et al. Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. J. Neurosci. 23, 230–239 (2003).

  14. 14.

    , , & Neuregulins increase alpha7 nicotinic acetylcholine receptors and enhance excitatory synaptic transmission in GABAergic interneurons of the hippocampus. J. Neurosci. 21, 5660–5669 (2001).

  15. 15.

    , , , & Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature 390, 691–694 (1997).

  16. 16.

    & Neuregulin1 down-regulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. Hippocampus, DOI: 10.1002/hipo.10185 (2003).

  17. 17.

    et al. Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877–892 (2002).

  18. 18.

    et al. Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J. Neurosci. 19, 10757–10766 (1999).

  19. 19.

    , , & Neuregulin and erbB receptor expression in normal and diseased human white matter. J. Neuroimmunol. 100, 233–242 (1999).

  20. 20.

    , & Failure of spinal cord oligodendrocyte development in mice lacking neuregulin. Proc. Natl. Acad. Sci. USA 96, 731–735 (1999).

  21. 21.

    et al. Evidence that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 28, 81–90 (2000).

  22. 22.

    et al. Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro. J. Neurosci. 21, 4740–4751 (2001).

  23. 23.

    et al. erbB3 is dispensable for oligodendrocyte development in vitro and in vivo. Glia 44, 67–75 (2003).

  24. 24.

    , , , & A role for the acetylcholine receptor-inducing protein ARIA in oligodendrocyte development. Proc. Natl. Acad. Sci. USA 91, 11626–11630 (1994).

  25. 25.

    et al. GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 17, 229–243 (1996).

  26. 26.

    et al. Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. Arch. Gen. Psychiatry 53, 425–436 (1996).

  27. 27.

    et al. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J. Neurosci. 16, 19–30 (1996).

  28. 28.

    , , , & Distribution of microtubule-associated protein MAP2-immunoreactive interstitial neurons in the parahippocampal white matter in subjects with schizophrenia. Am. J. Psychiatry 160, 149–155 (2003).

  29. 29.

    , & Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia. Neuropsychopharmacology 27, 826–833 (2002).

  30. 30.

    , , & Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427–436 (1999).

  31. 31.

    , , , & Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc. Natl. Acad. Sci. USA 95, 15066–15071 (1998).

  32. 32.

    et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl. Acad. Sci. USA 98, 4746–4751 (2001).

  33. 33.

    , , , & Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000).

  34. 34.

    , , , & Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch. Gen. Psychiatry 57, 237–245 (2000).

  35. 35.

    , , , & GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am. J. Psychiatry 158, 256–265 (2001).

  36. 36.

    et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res. Bull. 55, 597–610 (2001).

  37. 37.

    et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362, 798–805 (2003).

  38. 38.

    , , , & Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem. Res. 27, 1193–1200 (2002).

  39. 39.

    et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol. Psychiatry 53, 1075–1085 (2003).

  40. 40.

    et al. Dysregulated brain development in adult men with schizophrenia: a magnetic resonance imaging study. Biol. Psychiatry 53, 412–421 (2003).

  41. 41.

    et al. Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol. Psychiatry 8, 811–820 (2003).

  42. 42.

    et al. Investigating regional white matter in schizophrenia using diffusion tensor imaging. Neuroreport 13, 333–336 (2002).

  43. 43.

    & Pubertal neurodevelopment and the emergence of psychotic symptoms. Schizophr. Res. 54, 17–23 (2002).

  44. 44.

    , , & Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol. Psychiatry 38, 22–33 (1995).

  45. 45.

    et al. Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus. J. Neurochem. 73, 1590–1597 (1999).

  46. 46.

    , , & Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport 10, 1779–1782 (1999).

  47. 47.

    et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am. J. Hum. Genet. 72, 83–87 (2003).

  48. 48.

    et al. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol. Psychiatry 8, 485–487 (2003).

  49. 49.

    , , , & Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).

  50. 50.

    et al. Association study of neuregulin 1 gene with schizophrenia. Mol. Psychiatry 8, 706–709 (2003).

  51. 51.

    et al. Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol. Psychiatry 9, 11–12 (2004).

  52. 52.

    et al. No association with the neuregulin 1 haplotype to Japanese schizophrenia. Mol. Psychiatry 9, 126–127 (2004).

  53. 53.

    et al. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol. Psychiatry 21, 21 (2003).

  54. 54.

    & Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol. (Berl) 92, 217–231 (1996).

  55. 55.

    The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122, 593–624 (1999).

  56. 56.

    & The GABAergic system in schizophrenia. Int. J. Neuropsychopharmacol. 5, 159–179 (2002).

  57. 57.

    & Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol. Ther. 97, 153–179 (2003).

  58. 58.

    & GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27 (2001).

  59. 59.

    Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27, 672–683 (2002).

  60. 60.

    et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch. Gen. Psychiatry 60, 443–456 (2003).

  61. 61.

    , , , & Gene expression profiling with DNA microarrays: advancing our understanding of psychiatric disorders. Neurochem. Res. 27, 1049–1063 (2002).

  62. 62.

    , & The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry 2, 8 (2002).

  63. 63.

    Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr. Scand. Suppl. 232, 1–173 (1972).

  64. 64.

    & Schizophrenia: a disconnection syndrome? Clin. Neurosci. 3, 89–97 (1995).

  65. 65.

    et al. Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch. Gen. Psychiatry 55, 1084–1091 (1998).

Download references

Acknowledgements

Supported by the National Institute of Neurological Disorders and Stroke (R01 NS35884 to G.C.) and a Conte Center Grant (National Institute of Mental Health P50 MH066392 to J.D.B.). We thank J.N. Hirschhorn for help with meta-analysis of the genetic data and A. Rosenbaum for help with the illustration.

Author information

Affiliations

  1. Gabriel Corfas and Kristine Roy are in the Division of Neuroscience, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Gabriel Corfas
    •  & Kristine Roy
  2. Joseph D. Buxbaum is in the Departments of Psychiatry and Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA.

    • Joseph D Buxbaum

Authors

  1. Search for Gabriel Corfas in:

  2. Search for Kristine Roy in:

  3. Search for Joseph D Buxbaum in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gabriel Corfas.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nn1258

Further reading