title: Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill 27599, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Maynard
authors.forename: L
authors.initials: L
authors.lastname: Sikich
authors.forename: J A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: A S
authors.initials: AS
authors.lastname: LaMantia
mesh_terms: D001921:Brain / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology*; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004777:Environment; D006801:Humans; D009434:Neural Pathways / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D011582:Psychological Theory; D012559:Schizophrenia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D014212:Tretinoin / Q000009:adverse effects
chemical_list: D014212:Tretinoin