title: Phenotypic characterization of transgenic mice overexpressing neuregulin-1.
abstract: BACKGROUND
  Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants.
  
  
  RESULTS
  To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1α gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus.
  
  
  CONCLUSIONS
  These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasai
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.forename: Liang
authors.initials: L
authors.lastname: Fengyi
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.forename: Sadaaki
authors.initials: S
authors.lastname: Maeda
authors.forename: Minesuke
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Miwako
authors.initials: M
authors.lastname: Ozaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018076:DNA, Complementary / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D018076:DNA, Complementary; D020890:Neuregulin-1; D004298:Dopamine