Prophylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice

PLoS One. 2012;7(12):e51562. doi: 10.1371/journal.pone.0051562. Epub 2012 Dec 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / genetics*
  • Animals
  • Antimanic Agents / pharmacology
  • Behavior, Animal
  • Crosses, Genetic
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Glial Fibrillary Acidic Protein / biosynthesis
  • Hippocampus / metabolism
  • Homozygote
  • Lipocalin-2
  • Lipocalins / genetics*
  • Locomotion
  • Mice
  • Microscopy, Confocal / methods
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Neuroglia / cytology
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins / genetics*
  • Phenotype
  • RNA / metabolism
  • Schizophrenia / genetics
  • Schizophrenia / prevention & control*
  • Valproic Acid / pharmacology*


  • Acute-Phase Proteins
  • Antimanic Agents
  • Disc1 protein, mouse
  • Glial Fibrillary Acidic Protein
  • Lipocalin-2
  • Lipocalins
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • Lcn2 protein, mouse
  • Valproic Acid
  • RNA