Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice

Schizophrenia is a serious mental illness most notably characterized by psychotic symptoms. In humans, psychotic disorders are associated with specific hippocampal pathology. However, animal model systems for psychosis often lack this pathology, and have been weak in providing a representation of psychosis. We utilized a double-risk model system combining genetic risk with environmental stress. We hypothesized these factors will induce hippocampal subfield pathology consistent with human findings, as well as behavioral phenotypes relevant to psychosis. To address this, we exposed wild-type and transgenic Disc1 dominant negative (Disc1-deficient) mice to maternal deprivation. In adulthood, hippocampal subfields were examined for signs of cellular and behavioral pathology associated with psychosis. Mice exposed to maternal deprivation showed a decrease in dentate gyrus activity, and an increase in CA3/CA1 activity. Furthermore, results demonstrated a differential behavioral effect between maternal deprivation and Disc1 deficiency, with maternal deprivation associated with a hyperactive phenotype and impaired prepulse inhibition, and Disc1 deficiency causing an impairment in fear conditioning. These results suggest distinct consequences of environmental and genetic risk factors contributing to psychosis, with maternal deprivation inducing a state more wholly consistent with schizophrenia psychosis. Further research is needed to determine if this pathology is causally related to a specific behavioral phenotype. The development of a strong inference animal model system for psychosis would satisfy a high medical need in schizophrenia research.