Neural development, cell-cell signaling, and the two-hit hypothesis of schizophrenia

To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the two-hit hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a second hit that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as In the limbs and face, could be targets for a first hit during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a second hit in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a first hit may prime the CNS for a pathologic response to a second hit via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia.