Maternal Immune Activation during Gestation Interacts withDisc1Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice

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Abstract
Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors.DISC1is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouseDisc1gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) andDisc1-Q31L+/−offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age.Disc1-L100P+/−mutants were more sensitive to MIA than WT or Disc1-Q31L+/−mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain inDisc1-L100P+/−mice compared with WT orDisc1-Q31L+/−mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes inDisc1-L100P+/−mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P+/−) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.

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