Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood

Behav Brain Res. 2010 Jan 5;206(1):32-7. doi: 10.1016/j.bbr.2009.08.027. Epub 2009 Aug 28.


Gene-environment interaction may play a role in the etiology of schizophrenia. Transgenic mice expressing dominant-negative DISC1 (DN-DISC1 mice) show some histological and behavioral endophenotypes relevant to schizophrenia. Viral infection during neurodevelopment provides a major environmental risk for schizophrenia. Neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C), which mimics innate immune responses elicited by viral infection, leads to schizophrenia-like behavioral alteration in mice after puberty. To study how gene-environmental interaction during neurodevelopment results in phenotypic changes in adulthood, we treated DN-DISC1 mice or wild-type littermates with injection of polyI:C during the neonatal stage, according to the published method, respectively, and the behavioral and histological phenotypes were examined in adulthood. We demonstrated that neonatal polyI:C treatment in DN-DISC1 mice resulted in the deficits of short-term, object recognition, and hippocampus-dependent fear memories after puberty, although polyI:C treatment by itself had smaller influences on wild-type mice. Furthermore, polyI:C-treated DN-DISC1 mice exhibited signs of impairment of social recognition and interaction, and augmented susceptibility to MK-801-induced hyperactivity as compared with vehicle-treated wild-type mice. Of most importance, additive effects of polyI:C and DN-DISC1 were observed by a marked decrease in parvalbumin-positive interneurons in the medial prefrontal cortex. These results suggest that combined effect of neonatal polyI:C treatment and DN-DISC1 affects some behavioral and histological phenotypes in adulthood.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Behavior, Animal / physiology*
  • Cell Proliferation
  • Conditioning, Classical / physiology
  • Dizocilpine Maleate / toxicity
  • Fear / physiology
  • Female
  • Freezing Reaction, Cataleptic / physiology
  • Hippocampus / immunology*
  • Hippocampus / metabolism
  • Hyperkinesis / chemically induced
  • Hyperkinesis / genetics
  • Hyperkinesis / immunology
  • Immunohistochemistry
  • Interferon Inducers / administration & dosage
  • Ki-67 Antigen / metabolism
  • Male
  • Memory, Short-Term / physiology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Parvalbumins / metabolism
  • Phenotype*
  • Poly I-C / administration & dosage
  • Recognition, Psychology / physiology
  • Reflex, Startle / genetics
  • Reflex, Startle / immunology
  • Sensory Gating / genetics
  • Sensory Gating / immunology
  • Social Behavior
  • Staining and Labeling


  • Disc1 protein, mouse
  • Interferon Inducers
  • Ki-67 Antigen
  • Nerve Tissue Proteins
  • Parvalbumins
  • Dizocilpine Maleate
  • Poly I-C