Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180kDa. PFC cytoplasmic 53kDa NRG1 protein levels were significantly increased (~20%) in schizophrenic patients relative to each of the other subject groups. We also detected a trend towards diagnostic effects on PFC cytoplasmic full-length (180kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (~30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21kDa/180kDa and 55kDa/180kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4.

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