The goal of this project is to investigate the phenotype of a novel mouse model of schizophrenia (SCZ). Many genetic models of SCZ have been proposed, however, drug discovery has been limited and focused on treating symptoms of psychosis. We propose to evaluate a novel gene x environment interaction model of SCZ, and identify the common pathways contributing to disease development as novel targets for the development of therapeutics or prophylaxis. The glutamate pathway is a key contributor to the symptoms of SCZ, and our model represents multiple hits, genetic and environmental, to this pathway. We will subject mice with mutations in the Disrupted-in-Schizophrenia (DISC1) and Reelin (RELN) genes to prenatal immune activation using the viral mimetic Polyriboinosinic:polyribocytidylic acid (Poly I:C), and evaluate SCZ-like pathology and behavior. This is a highly salient model for SCZ, incorporating two distinct genetic mutations that are: 1) associated with SCZ; 2) produce similar neurobiological alterations; and 3) interact with immune activation to produce SCZ-relevant behavioral changes. Immune activation, while not a new area of study in relation to SCZ, has recently come under the spotlight with genetic susceptibility studies pinpointing complement component 4 (C4) genes as an important point of association between SCZ and variations in the major histocompatibility locus, and we expect this immune activation to exacerbate our SCZ phenotypes. This project bridges multiple SCZ hypotheses in a much needed integrative approach. We hypothesize that combined disruption of DISC1 and RELN will result in a more severe SCZ-like phenotype than either mutation alone, including behavioral and learning deficits, altered neurogenesis and dendritic morphology, and changes in complement pathway molecule expression; and these changes will be exacerbated by prenatal immune activation.
Aim 1 will characterize the behavioral endophenotype of mice expressing dominant negative truncated human DISC1, and 50% of the normal amount of reelin, as it relates to expected SCZ behavior. Our preliminary data indicates changes in affect and cognition.
Aim 2 will evaluate behavior with the addition of an environmental insult, prenatal immune activation, that is known to produce SCZ-like behavior, and to interact with both mutations individually.
Aim 3 will determine if there are changes in complement molecule expression, neurogenesis, and long-term potentiation following both genetic and environmental hits. As this is the first study to characterize this model of SCZ, positive or negative data will add to the body of knowledge about the underlying biology of SCZ.
In order to produce safe and effective treatments for schizophrenia, we need to better understand how to target the development of the disease. To this end, we propose to characterize the prenatal gene-environment interactions that increase susceptibility to the disease in our novel mouse model. This will allow us to identify new targets for drug discovery in schizophrenia.
