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Altered neuregulin 1–erbB4 signaling contributes to NMDA> receptor hypofunction in schizophrenia

An Editorial Expression of Concern to this article was published on 19 December 2023

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Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia1,2,3. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling4,5,6. Here, using a new postmortem tissue–stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4–PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

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Figure 1: The expression of NRG1 or erbB4 proteins is not altered in the PFC of subjects with schizophrenia (SCZ).
Figure 2: NRG1-induced erbB4 activation is increased in the PFC of SCZ subjects.
Figure 3: Association of erbB4 with PSD-95 is enhanced in the PFC of schizophrenic subjects.
Figure 4: NRG1 attenuation of NMDAR activation is greater in the schizophrenic subjects than in controls.

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Corvin, A.P. et al. 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, 208–213 (2004).

    Article  CAS  Google Scholar 

  4. Anton, E.S. et al. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat. Neurosci. 7, 1319–1328 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Ozaki, M., Sasner, M., Yano, R., Lu, H.S. & Buonanno, A. Neuregulin-β induces expression of an NMDA-receptor subunit. Nature 390, 691–694 (1997).

    Article  CAS  Google Scholar 

  7. Stefansson, H., Steinthorsdottir, V., Thorgeirsson, T.E., Gulcher, J.R. & Stefansson, K. Neuregulin 1 and schizophrenia. Ann. Med. 36, 62–71 (2004).

    Article  CAS  Google Scholar 

  8. Fischbach, G.D. & Rosen, K.M. ARIA: a neuromuscular junction neuregulin. Annu. Rev. Neurosci. 20, 429–458 (1997).

    Article  CAS  Google Scholar 

  9. Buonanno, A. & Fischbach, G.D. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 287–296 (2001).

    Article  CAS  Google Scholar 

  10. Lemke, G. Glial control of neuronal development. Annu. Rev. Neurosci. 24, 87–105 (2001).

    Article  CAS  Google Scholar 

  11. Arnold, S.E., Talbot, K. & Hahn, C.G. Neurodevelopment, neuroplasticity, and new genes for schizophrenia. Prog. Brain Res. 147, 319–345 (2005).

    Article  CAS  Google Scholar 

  12. Harrison, P.J. & Weinberger, D.R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10, 40–68 (2005).

    Article  CAS  Google Scholar 

  13. Rio, C., Rieff, H.I., Qi, P., Khurana, T.S. & Corfas, G. Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 19, 39–50 (1997).

    Article  CAS  Google Scholar 

  14. Okada, M. & Corfas, G. Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. Hippocampus 14, 337–344 (2004).

    Article  CAS  Google Scholar 

  15. Huang, Y.Z. et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26, 443–455 (2000).

    Article  CAS  Google Scholar 

  16. Gu, Z., Jiang, Q., Fu, A.K., Ip, N.Y. & Yan, Z. Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J. Neurosci. 25, 4974–4984 (2005).

    Article  CAS  Google Scholar 

  17. Hashimoto, R. et al. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol. Psychiatry 9, 299–307 (2004).

    Article  CAS  Google Scholar 

  18. Frenzel, K.E. & Falls, D.L. Neuregulin-1 proteins in rat brain and transfected cells are localized to lipid rafts. J. Neurochem. 77, 1–12 (2001).

    Article  CAS  Google Scholar 

  19. Wang, H.Y. & Friedman, E. Receptor-mediated activation of G proteins is reduced in postmortem brains from Alzheimer's disease patients. Neurosci. Lett. 173, 37–39 (1994).

    Article  CAS  Google Scholar 

  20. Wang, H.Y. & Friedman, E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol. Psychiatry 40, 568–575 (1996).

    Article  CAS  Google Scholar 

  21. Garcia, R.A., Vasudevan, K. & Buonanno, A. The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Natl. Acad. Sci. USA 97, 3596–3601 (2000).

    Article  CAS  Google Scholar 

  22. Clinton, S.M. & Meador-Woodruff, J.H. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 29, 1353–1362 (2004).

    Article  CAS  Google Scholar 

  23. Toyooka, K. et al. Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia. J. Neurochem. 83, 797–806 (2002).

    Article  CAS  Google Scholar 

  24. Coyle, J.T., Tsai, G. & Goff, D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann. NY Acad. Sci. 1003, 318–327 (2003).

    Article  CAS  Google Scholar 

  25. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

    Article  CAS  Google Scholar 

  26. Kwon, O.B., Longart, M., Vullhorst, D., Hoffman, D.A. & Buonanno, A. Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J. Neurosci. 25, 9378–9383 (2005).

    Article  CAS  Google Scholar 

  27. Harrison, P.J. & Owen, M.J. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361, 417–419 (2003).

    Article  CAS  Google Scholar 

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We express our gratitude to collaborating state hospitals of the Commonwealth of Pennsylvania, and, above all, to the patients and their families for their participation. We also acknowledge the clinical staff and residents of the Schizophrenia Research Center and Division of Medical Pathology at the University of Pennsylvania for subject assessment and autopsy. This work was supported by grants from the US National Institutes of Health (MH64045 and MH63946).

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Correspondence to Chang-Gyu Hahn.

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Supplementary information

Supplementary Fig. 1

NRG1 or NMDA stimulation activates intracellular signal transduction in postmortem brains. (PDF 50 kb)

Supplementary Fig. 2

NRG1 stimulation induces erbB4 activation in mouse brains at varied postmortem intervals. (PDF 65 kb)

Supplementary Fig. 3

Haloperidol treatment does not enhance NRG1 induced erbB4 activation. (PDF 64 kb)

Supplementary Fig. 4

Association of erbB4 with NMDAR is enhanced in PFCs of SCZ subjects. (PDF 53 kb)

Supplementary Fig. 5

Association of PSD-95 with NMDAR is enhanced in the PFC of SCZ subjects. (PDF 49 kb)

Supplementary Fig. 6

ErbB4 expression in human postmortem brains. (PDF 158 kb)

Supplementary Table 1

Demographic information on the subjects of postmortem brains. (PDF 70 kb)

Supplementary Note (PDF 152 kb)

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Hahn, CG., Wang, HY., Cho, DS. et al. Altered neuregulin 1–erbB4 signaling contributes to NMDA> receptor hypofunction in schizophrenia. Nat Med 12, 824–828 (2006).

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