Nature Medicine
- 12, 824 - 828 (2006)
Published online: 11 June 2006; | doi:10.1038/nm1418
Altered neuregulin 1–erbB4 signaling contributes to NMDA> receptor hypofunction in schizophreniaChang-Gyu Hahn1, 4, Hoau-Yan Wang2, 4, Dan-Sung Cho1, Konrad Talbot1, Raquel E Gur1, Wade H Berrettini1, Kalindi Bakshi2, Joshua Kamins1, Karin E Borgmann-Winter1, Steven J Siegel1, Robert J Gallop3 & Steven E Arnold11
Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 2
Department of Physiology and Pharmacology, City University of New York Medical School, 160 Convent Avenue, New York, New York 10031, USA. 3
Department of Mathematics, Applied Statistics Program, West Chester University, 323 Anderson Hall, West Chester, Pennsylvania 19380, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Chang-Gyu Hahn hahnc@mail.med.upenn.edu 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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