Schizophrenia is a devastating disorder with a worldwide prevalence of 0.5-1.2% [62
]. The disease generally presents in late adolescence and early adulthood [61
]. As a disorder of youth and adulthood, schizophrenia leads to significant loss of daily activity, reduced productivity and increased unemployment rates [131
]. The disease is associated with higher rates of violent behavior and higher rates of suicide, causing not only mental suffering for the patients but also significant difficulties for the caregivers. Schizophrenia poses a significant burden to the society, causing substantial excess of direct and indirect costs [131
]. Although the efforts to treat the disease have led to significant success starting from the second part of last century, the current treatment options are palliative only [71
For this chronic, debilitating disease known for thousands of years [114
], no test exists to identify affected individuals beyond the signs and symptoms of the disorder. Various disease-associated alterations have been noted, including enlargement of lateral and third ventricles, reduced volumes of medial temporal lobe and superior temporal gyrus, sensorimotor gating deficit, impaired cognitive modalities such as attention and working memory [101
]. However, neither in vivo
nor postmortem examinations can identify a specific morphological, biochemical or electrophysiological phenotype. Indeed, the cause of the disorder remains unknown, possibly with multiple factors contributing to the disease generation. We believe that experimental models may help enlighten the etiology and pathogenic mechanisms of the disorder and ultimately facilitate new therapeutic treatments.
The etiology of schizophrenia is complex [78
]. The heritability estimates of schizophrenia are between 60-80% [1
]. The variance is explained by both genetic factors and shared and unique environmental effects [70
]. The early environmental factors most frequently associated with schizophrenia are maternal prenatal infections (CMV, influenza, rubella, toxoplasma), winter/early spring birth, preterm birth and obstetric complications (mostly related to hypoxia), urban living and adolescent cannabis use [123
]. Although the associations with these factors were demonstrated to a various degree in different cohorts, no specific environmental factor is able to explain the majority of cases of schizophrenia. Thus, it has been proposed that interactions between genetic and environmental factors may play a leading role in the pathogenesis of this mental illness [20
There have been numerous studies suggestive of interactions between environmental and genetic factors in schizophrenia [19
]. However, epidemiological studies in humans have not been able to address the mechanisms whereby gene-environment interactions (GEI) occur. Several approaches to evaluate the GEI in animal models of schizophrenia have been proposed, although there is still a need for refinement and further development of animal models pertinent to the pathogenesis of schizophrenia and related mental diseases. Here, we will critically evaluate the most popular approaches to GEI animal models of schizophrenia, and propose that establishing animal and cell models based on interactions of the relevant mutant genes and measurable environments will likely stimulate mechanistic studies.