Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.
Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. 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 signaling. 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.
Hahn
Chang-Gyu
CG
Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. hahnc@mail.med.upenn.edu
Wang
Hoau-Yan
HY
Cho
Dan-Sung
DS
Talbot
Konrad
K
Gur
Raquel E
RE
Berrettini
Wade H
WH
Bakshi
Kalindi
K
Kamins
Joshua
J
Borgmann-Winter
Karin E
KE
Siegel
Steven J
SJ
Gallop
Robert J
RJ
Arnold
Steven E
SE
D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002102:Cadaver; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D020890:Neuregulin-1 / Q000502:physiology*; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology; D066247:Receptor, ErbB-4; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012559:Schizophrenia / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction
D020890:Neuregulin-1; D016194:Receptors, N-Methyl-D-Aspartate; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4