title: Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice.
abstract: BACKGROUND
  Disrupted-in-Schizophrenia 1 (DISC1) is considered to be a candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. A recent study reported that N-ethyl-N-nitrosourea (ENU)-induced mutations in exon 2 of the mouse Disc1 gene, which resulted in the amino acid exchange of Q31L and L100P, caused an increase in depression-like behavior in 31 L mutant mice and schizophrenia-like behavior in 100P mutant mice; thus, these are potential animal models of psychiatric disorders. However, remaining heterozygous mutations that possibly occur in flanking genes other than Disc1 itself might induce behavioral abnormalities in the mutant mice. Here, to confirm the effects of Disc1-Q31L and Disc1-L100P mutations on behavioral phenotypes and to investigate the behaviors of the mutant mice in more detail, the mutant lines were backcrossed to C57BL/6JJcl through an additional two generations and the behaviors were analyzed using a comprehensive behavioral test battery.
  
  
  RESULTS
  Contrary to expectations, 31 L mutant mice showed no significant behavioral differences when compared with wild-type control mice in any of the behavioral tests, including the Porsolt forced swim and tail suspension tests, commonly used tests for depression-like behavior. Also, 100P mutant mice exhibited no differences in almost all of the behavioral tests, including the prepulse inhibition test for measuring sensorimotor gating, which is known to be impaired in schizophrenia patients; however, 100P mutant mice showed higher locomotor activity compared with wild-type control mice in the light/dark transition test.
  
  
  CONCLUSIONS
  Although these results are partially consistent with the previous study in that there was hyperactivity in 100P mutant mice, the vast majority of the results are inconsistent with those of the previous study; this discrepancy may be explained by differences in the genetic background of the mice, the laboratory environment, experimental protocols, and more. Further behavioral studies under various experimental conditions are necessary to determine whether these Disc1 mutant mouse lines are suitable animal models of schizophrenia and major depression.
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shoji
authors.forename: Keiko
authors.initials: K
authors.lastname: Toyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takamiya
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D019943:Amino Acid Substitution / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003866:Depressive Disorder / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D012919:Social Behavior
chemical_list: D000477:Alkylating Agents; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D005038:Ethylnitrosourea