Future of Days Past: Neurodevelopment and Schizophrenia

Since a proposal in 1986 that schizophrenia involved early neurodevelopmental deviations beginning in intrauterine life that showed varying expressivity as relevant neural systems matured, our understanding of the developmental components of the pathogenesis of schizophrenia has substantially evolved. This commentary highlights recent genetic and epigenetic evidence that prenatal development is a critical period for the expression of schizophrenia risk. Studies of gene expression have been fairly consistent in showing that genes implicated in schizophrenia show relatively greater expression during fetal than postnatal life. Consistent molecular evidence of early environmental perturbations contributing to risk has emerged from studies of epigenetic marks in the brain genome as potential environmental footprints and these also highlight the prenatal period. Analyses of gene expression in placenta dramatically identify the intrauterine environment as a direct point of impact of a component of schizophrenia genetic risk. Together, the enrichment of transcriptional and epigenetic associations with schizophrenia during fetal life suggest that both genetic and environmental risk for schizophrenia have a particular molecular impact on early development, possibly because of genetic biases in environmental sensitivity.