title: Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse.
abstract: BACKGROUND
  The Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse. In addition, we investigate the regulation of high-frequency (gamma) electrophysiological oscillations in this mutant mouse to associate molecular changes in Nrg1 with a schizophrenia-relevant neurophysiological profile.
  
  
  METHODS
  Using exonic probes spanning the cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and intracellular domain encoding regions of Nrg1, mRNA levels were measured using qPCR in hippocampus and frontal cortex from male and female Nrg1 TM HET and wild type-like (WT) mice throughout development. We also performed electrophysiological recordings in adult mice and analysed gamma oscillatory at baseline, in responses to auditory stimuli and to ketamine.
  
  
  RESULTS
  In both hippocampus and cortex, Nrg1 TM HET mice show significantly reduced expression of the exon encoding the transmembrane domain of Nrg1 compared with WT, but unaltered mRNA expression encoding the extracellular bioactive EGF-like and the cysteine-rich (type III) domains, and development-specific and region-specific reductions in the mRNA encoding the intracellular domain. Hippocampal Nrg1 protein expression was not altered, but NMDA receptor NR2B subunit phosphorylation was lower in Nrg1 TM HET mice. We identified elevated ongoing and reduced sensory-evoked gamma power in Nrg1 TM HET mice.
  
  
  CONCLUSIONS
  We found no evidence to support the claim that the Nrg1 TM HET mouse represents a simple haploinsufficient model. Further research is required to explore the possibility that mutation results in a gain of Nrg1 function.
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Leonora E
authors.initials: LE
authors.lastname: Long
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; University of Wollongong, Wollongong, New South Wales, Australia.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Frank
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Shaw
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; University of Wollongong, Wollongong, New South Wales, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: INSERM U1114, psychopathologie cognitive et physiopathologie de la schizophrénie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Pinault
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Karl
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Shannon Weickert
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D004569:Electroencephalography; D005260:Female; D006579:Heterozygote; D008124:Locomotion; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020890:Neuregulin-1 / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate