title: Elevated ErbB4 mRNA is related to interneuron deficit in prefrontal cortex in schizophrenia.
abstract: Neuregulin 1 and its receptor ErbB4 are confirmed risk genes for schizophrenia, but the neuropathological alterations in NRG1-ErbB4 in schizophrenia are unclear. The present investigations therefore focused on determining lamina specific (ErbB4-pan) and quantitative (pan, JMa, JMb, CYT1 and CYT2) ErbB4 mRNA changes in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We also determined which neuronal profiles are ErbB4 mRNA+ in the human DLPFC and the relationship between ErbB4 and interneuron marker mRNAs. In situ hybridisation and quantitative PCR measurements were performed to determine changes in ErbB4 splice variant mRNA levels in the DLPFC in schizophrenia (n = 37) compared to control (n = 37) subjects. Cortical neurons expressing ErbB4-pan were labelled with silver grain clusters. Correlations were performed between ErbB4 and interneuron mRNA levels. ErbB4-pan mRNA was significantly increased (layers I, II and V) in the DLPFC in schizophrenia. Silver grain clusters for ErbB4-pan were detected predominantly over small-medium neurons with low-no expression in the larger, paler, more triangular neuronal profiles. ErbB4-JMa mRNA expression was increased in schizophrenia. Somatostatin, neuropeptide Y and vasoactive intestinal peptide mRNAs negatively correlated with ErbB4-JMa mRNA in people with schizophrenia. Our findings demonstrate that ErbB4-pan laminar mRNA expression is elevated (layers I, II, V) in schizophrenia. At the cellular level, ErbB4-pan mRNA+ signal was detected predominantly in interneuron-like neurons. We provide evidence from this independent Australian postmortem cohort that ErbB4-JMa expression is elevated in schizophrenia and is linked to deficits in dendrite-targeting somatostatin, neuropeptide Y and vasoactive intestinal peptide interneurons.
authors.affiliation: Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia; Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Joshi
authors.affiliation: Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia; Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Fullerton
authors.affiliation: Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia; Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: c.weickert@neura.edu.au.
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007395:Interneurons / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000473:pathology*; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D009478:Neuropeptide Y; D012333:RNA, Messenger; D014660:Vasoactive Intestinal Peptide; D013004:Somatostatin; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4
keywords: ErbB4; Interneuron; Messenger RNA; Prefrontal cortex; Schizophrenia; Splice variant