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

To account for the complex genetics, the developmental biology, and the lat e adolescent/early adulthood onset of schizophrenia, the "two-hit" hypothes is has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These earl y disruptions produce long-term vulnerability to a "second hit" that then l eads to the onset of schizophrenia symptoms. The cell-cell signaling pathwa ys involved in nonaxial induction, morphogenesis, and differentiation in th e brain, as well as In the limbs and face, could be targets for a "first hi t" during early development. These same pathways, redeployed for neuronal m aintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-cell sign aling by a "first hit" may prime the CNS for a pathologic response to a "se cond hit" via the same signaling pathway. Thus, parallel disruption of cell -cell signaling in both the developing and the mature CNS provides a plausi ble way of integrating genetic, developmental, and environmental factors th at contribute to vulnerability and pathogenesis in schizophrenia.