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Clue to Schizophrenia Late Manifestation from Early Developmental Changes

Scientists from Johns Hopkins and collaborating institutions have discovered a clue as to how schizophrenia might develop after puberty as the result of genetic influences that occur in early development. In a new study, the researchers have manipulated (knocked down) a known schizophrenia susceptibility gene (DISC-1) in the brains of fetal mice in an attempt to unravel the complex link between prenatal brain development and the maturation of information processing and cognition in adult animals. The scientists showed that a transient reduction of DISC-1 (disrupted in schizophrenia-1) gene expression in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia--including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities. These findings are significant because they provide a concrete link between a nonlethal genetic disruption during prenatal brain development and specific abnormalities in adult brain maturation. "Prior to our study, the kinds of neurodevelopmental defects that cause the defined anatomical changes observed in schizophrenia patients--clinical onset 15+ years after birth, psychosis, impaired cognition and information processing, and aberrant dopaminergic neurotransmission--were not clear," offered Dr. Toshitaka Nabeshima, the senior author of the report. "However, the model in our study represents a majority of these characteristics.” The authors were careful to caution that while their findings shed some light on how early disease-associated events impact adult brain function, manipulation of one gene cannot fully define the complex neuropathology associated with schizophrenia. "Although it is only one piece of the puzzle, our study may aid molecular understanding of how the initial insults during early development disturb postnatal brain maturation for many years, which results in full-blown onset of schizophrenia or other mental disorders after puberty," explained Dr. Akira Sawa, an author of the report. The study results were presented in the February 25 issue of Neuron. [Press release] [Neuron abstract]