© 2001 by Oxford University Press and the Maryland Psychiatric Research Center (MPRC)
Neural Development, Cell-Cell Signaling, and the "Two-Hit" Hypothesis of Schizophrenia
Department of Cell and Molecular Physiology in the School of Medicine of the University of North Carolina (UNC) Chapel Hill, NC
Department of Psychiatry of the School of Medicine at the University of North Carolina Chapel Hill, NC
Department of Psychiatry of the School of Medicine at the University of North Carolina Chapel Hill, NC
Associate Professor of Cell and Molecular Physiology and a member of the UNC Neuroscience Center
Send reprint requests to Dr. A.-S. LaMantia, 260 MSRB, CB#7545, Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599; e-mail: anthony_lamantia{at}med.unc.edu
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.
Keywords: Development / signaling / schizophrenia / genetics / teratogenesis / neuronal circuits
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