title: Prophylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice.
abstract: BACKGROUND
  Schizophrenia is a neurodevelopmental disorder with onset early in adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptibility gene for schizophrenia and other psychiatric disorders. Disc1-L100P mutant mice show behaviors relevant to schizophrenia at 12 weeks, but not at 8 weeks of age, and may be useful for investigating the onset of schizophrenia in early adulthood.
  
  
  METHODS
  We investigated whether early valproic acid treatment would prevent behavioral, cellular and gene expression abnormalities in Disc1-L100P mutants.
  
  
  RESULTS
  Valproic acid prevented hyperactivity and deficits in prepulse inhibition and latent inhibition in Disc1-L100P mice. Genome-wide transcription profiling identified Lcn2 (lipocalin2) transcripts as being elevated by the Disc1 mutation and corrected by valproate. Disc1-L100P mice also had increased glial cell numbers in the subventricular zone, which was normalized by valproate. Genetic deletion of Lcn2 normalized glial cell numbers and behavior in Disc1-L100P mutants.
  
  
  CONCLUSIONS
  Pharmacological treatments are a feasible way of preventing abnormal behaviour in a genetic model of schizophrenia. Lcn2 is a potential novel drug target for early intervention in schizophrenia.
authors.affiliation: Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Lipina
authors.forename: Fahmida Nipa
authors.initials: FN
authors.lastname: Haque
authors.forename: Alexander
authors.initials: A
authors.lastname: McGirr
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001522:Behavior, Animal; D003433:Crosses, Genetic; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism; D006720:Homozygote; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics*; D008124:Locomotion; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000517:prevention & control*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000209:Acute-Phase Proteins; D018692:Antimanic Agents; C498794:Disc1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D000071068:Lipocalin-2; D054834:Lipocalins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse; D014635:Valproic Acid; D012313:RNA