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

Nature Medicine volume 12, pages 824–828 (2006)Cite this article

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

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Abstract

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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Acknowledgements

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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Author notes

  1. Chang-Gyu Hahn and Hoau-Yan Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Chang-Gyu Hahn, Dan-Sung Cho, Konrad Talbot, Raquel E Gur, Wade H Berrettini, Joshua Kamins, Karin E Borgmann-Winter, Steven J Siegel & Steven E Arnold

  2. Department of Physiology and Pharmacology, City University of New York Medical School, 160 Convent Avenue, New York, 10031, New York, USA

    Hoau-Yan Wang & Kalindi Bakshi

  3. Department of Mathematics, Applied Statistics Program, West Chester University, 323 Anderson Hall, West Chester, 19380, Pennsylvania, USA

    Robert J Gallop

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  1. Chang-Gyu Hahn
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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). https://doi.org/10.1038/nm1418

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