Decanalization mediating gene-environment interactions in schizophrenia and other psychiatric disorders with neurodevelopmental etiology

OVERVIEW Schizophrenia provides a striking example of a disorder in which complex genetic and environmental factors combine to produce abnormal brain development and function. In order to fully understand the disorder, and develop more effective and targeted treatments, more accurate and sophisticated animal models are required, which incorporate genetic and environmental variables and their associated gene-environment interactions. We discuss key considerations in modeling gene-environment interactions, with a focus on the recent proposal that schizophrenia involves “decanalization,” whereby “experience-expectant” brain development can have its trajectory derailed when particular genotypes (and associated cryptic genetic variants) are exposed to “unexpected” environmental conditions. This has broader implications for the modeling of schizophrenia and other brain disorders involving neurodevelopmental etiology, including autism spectrum disorders (ASDs). We propose that it is insufficient to examine animal models expressing particular genetic variants or mutations only in the single environmental context of “standard” housing conditions. The exploration of disease-associated polymorphisms and mutations under housing conditions in which environmental