Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Abstract

Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and b-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.

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

“…These findings appear consistent with previous reports showing isoform-specific increases in PFC NRG1 and ErbB4 mRNA levels in schizophrenia (Hashimoto et al 2004;Law et al 2007;Silberberg et al 2006). Furthermore, none of the analyzed PFC NRG1 and ErbB4 immunoreactive fragments were altered in major depressed or bipolar subjects, suggesting the schizophrenia-associated PFC increases in NRG1-ICD and full-length ErbB4 protein levels were specific to schizophrenia.…”

“…If our findings do reflect the schizophrenia-associated NRG1 and ErbB4 mRNA elevations reported previously, then the NRG1-ICD protein we detected would be expected to be derived from the type I isoform (Hashimoto et al 2004;Law et al 2006) while the full-length ErbB4 protein we observed would be expected to consist of JMa and/or Cyt1 domains (Law et al 2007;Silberberg et al 2006). Based on these assumptions, our observations would support previous evidence of enhanced PFC NRG1-ErbB4 signaling in schizophrenia (Hahn et al 2006) because the extracellular domains of both NRG1 type I and JMa-containing ErbB4 isoforms can be cleaved to activate membrane-bound ErbB4 and NRG1, respectively (Bao et al 2003;Carpenter 2003;Falls 2003).…”

“…Our previous finding of schizophrenia-associated NRG1 mRNA increases (Hashimoto et al 2004;Law et al 2006) suggests elevated transcription may contribute to the increased PFC cytoplasmic NRG1-ICD levels in schizophrenia. However, the relation between NRG1 mRNA isoforms and the NRG1-ICD we detected is unclear.…”

“…Mice in which NRG1 and ErbB4 expression is reduced exhibit schizophrenia-associated phenotypes (Stefansson et al 2002), while the prefrontal cortex (PFC) of schizophrenic subjects exhibit NRG1α protein reductions (Bertram et al 2007). However, isoform-specific increases in PFC NRG1 and ErbB4 mRNA expression have also been observed in these patients (Hashimoto et al 2004;Law et al 2006;Law et al 2007;Silberberg et al 2006). Thus, it appears changes in brain NRG1 and/or ErbB4 levels may play roles in schizophrenia, although altered ErbB4 activation with no significant changes in NRG1 and ErbB4 protein quantities has recently been shown in patient brains (Hahn et al 2006).…”

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…Expression of type I-containing isoforms were elevated in schizophrenia. 6,7 Moreover, a singlenucleotide polymorphism (SNP; SNP8NRG243177) and a four-marker haplotype (both derived from the Icelandic haplotype) were significantly associated with the expression of type IV neuregulin isoforms in the brain, with the risk allele or haplotype associated with increased expression of these isoforms. 7 NRG1 gene products can activate intracellular signaling pathways through interactions with members of the ERB family of receptor tyrosine kinases (ERBB2, ERBB3 and ERBB4).…”