Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Abstract

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.

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

“…However, current results do not support this claim, since the majority of post-mortem studies in schizophrenia have found no correlation between overexpressions of NRG1/ErbB4 and dosages of antipsychotic treatment (Chong et al, 2008;Hahn et al, 2006;Hashimoto et al, 2004;Law et al, 2007;Law et al, 2006). Furthermore, elevated expression of the NRG1 intracellular part was only observed in the PFC of schizophrenia, but not bipolar disorders and depression, although bipolar patients were also exposed to antipsychotics (Chong et al, 2008). Positive associations between intronic SNPs (rs7598440, rs707284, rs839523) and elevated mRNA expressions of ErbB4 isoforms containing a metalloprotease cleavable extracellular domain (JM-a) and CYT-1 domain have been reported, which suggests a splice-variant specific expression of ErbB4 in the brain in schizophrenia (Law et al, 2007).…”

“…It should be noted that schizophrenia patients usually have undergone chronic antipsychotic treatments, therefore one key question is whether elevated NRG1-ErbB4 signalling observed in post-mortem studies is caused by antipsychotic treatment. However, current results do not support this claim, since the majority of post-mortem studies in schizophrenia have found no correlation between overexpressions of NRG1/ErbB4 and dosages of antipsychotic treatment (Chong et al, 2008;Hahn et al, 2006;Hashimoto et al, 2004;Law et al, 2007;Law et al, 2006). Furthermore, elevated expression of the NRG1 intracellular part was only observed in the PFC of schizophrenia, but not bipolar disorders and depression, although bipolar patients were also exposed to antipsychotics (Chong et al, 2008).…”

“…Bertram et al 2007 The NRG1 isoform expression is significantly reduced in white matter and gray matter of the PFC of schizophrenia patients. Chong et al, 2008 NRG1 expression increased in the PFC of schizophrenia patients. Parlapani et al, 2010 (1) Expression of NRG1 type I decreased in BA10 of schizophrenia patients.…”

“…In a following study, the levels of mRNA for NRG1 type I was confirmed to be elevated (34%) in the hippocampus of schizophrenia patients . Importantly, Chong et al have also found that the protein level of the NRG1 intracellular part increased by about 20% only in the PFC of schizophrenia patients, but not in patients with bipolar disorders and depression (Chong et al, 2008). In contrast, a recent study demonstrated that the gene expression of NRG1 type I isoform decreased in the PFC, Brodmann area 10 (BA10) (53.2%), and the expression of NRG1 type II isoform increased in BA10 (193%) of elderly schizophrenia patients (Parlapani et al, 2010).…”

“…A post-mortem study has shown that the protein expression of the full-length ErbB4 receptor was increased by nearly 30% in the PFC of schizophrenia patients (Chong et al, 2008). In addition, another study has reported that the expression of ErbB4 receptor isoforms that contain the C-terminal cytoplasmic tails (CYT)-1 domain significantly increased in the dorsolateral PFC of schizophrenia patients (Silberberg et al, 2006).…”