title: Reversible overexpression of bace1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice.
abstract: BACKGROUND
  Neuregulin-1 (Nrg1) is a pleiotropic signaling molecule that regulates neural development, and mutation of Nrg1 is a risk factor for schizophrenia. Cleavage of type I β1 Nrg1 isoform by Bace1 releases a secreted N-terminal fragment (Nrg1-ntfβ), which can bind to a cognate ErbB receptor to activate the specific signaling cascade. This study aimed to determine whether increased expression of Nrg1 is beneficial for brain development and functions.
  
  
  METHODS
  We generated transgenic mice overexpressing this fragment under the control of a tetracycline-inducible promoter and examined functional and behavioral changes in mice upon reversible expression of the transgene.
  
  
  RESULTS
  Increased expression of full-length Nrg1 in mouse neurons has been previously shown to enhance myelination in the central nervous system. Overexpressing Nrg1-ntfβ enhanced the expression of myelin proteins, consistent with the expected activation of the Nrg1 signaling pathway by Nrg1-ntfβ. Contrary to expectations, overexpressing Nrg1-ntfβ transgene caused schizophrenia-like behaviors in transgenic mice, and these abnormal behaviors were reversible if the expression of the Nrg1-ntfβ transgene was turned off. Our molecular assay suggests that protein levels of N-methyl-D-aspartate receptors are reduced in this transgenic mouse model, which might underlie the observed social and cognitive behavioral impairments.
  
  
  CONCLUSIONS
  Our results indicate that overexpressing the secreted form of Nrg1 is sufficient to cause schizophrenia-like behaviors in a mouse model, meaning the effect is independent of the transmembrane and C-terminal domains of Nrg1. Hence, genetic gain-of-function mutations of Nrg1 are also risk factors for schizophrenia.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Wanxia
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address: yanr@ccf.org.
authors.forename: Riqiang
authors.initials: R
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000737:chemistry* / Q000235:genetics*; D010641:Phenotype; D017470:Receptors, Glutamate / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D020890:Neuregulin-1; D017470:Receptors, Glutamate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Bace1; NMDA receptor; neuregulin; schizophrenia; tetracycline control expression; transgenic mice