Expression of Behavioral Phenotypes in Genetic and Environmental Mouse Models of Schizophrenia

Schizophrenia is a neuropsychiatric disorder characterized by multifactorial etiology involving complex interactions among genetic and environmental factors. “Multiple-hit” models of the disorder can explain its variable incidence and prevalence in related individuals. Hence, there is a dire need to understand these interactions in the emergence of schizophrenia. To test these factors in the emergence of schizophrenia-like behaviors, we employed a genetic mouse model of the disorder (harboring the DISC1 mutation) along with various environmental insults, such as early life stress (maternal separation of pups) and/or pharmacological interventions (ketamine injections). When assessed on a battery of behavioral tests, we found that environmental interventions affect the severity of behavioral phenotypes in terms of increased negative behavior, as shown by reduced mobility in the forced swim and tail suspension tests, and changes to positive and cognitive symptoms, such as increased locomotion and disrupted PPI along with reduced working memory, respectively. Among the various interventions, the genetic mutation had the most profound effect on behavioral aberrations, followed by an environmental intervention by ketamine injections and ketamine-injected animals that were maternally separated during early postnatal days. We conclude that although environmental factors increased the prevalence of aberrant behavioral phenotypes, genetic background is still the predominant influence on phenotypic alterations in these mouse models of schizophrenia.