probands relative to their healthy relatives could account for our finding that the higher-functioning Val allele is associated with more persistent CT deficits in COS probands than in unaffected SIBs. Although highly speculative, this proposal has implications for the two most prominent theories of schizophrenia—the “dopamine hypothesis” and the “developmental hypothesis” (Murray et al., 2008). Dopamine dysregulation in those at manifest and latent risk for schizophrenia is most commonly studied with respect to its potential to cause dysfunction within meso-cortical, meso-striatal and meso-limbic circuits that are thought to underlie many of the cardinal clinical features of the syndrome (Howes and Kapur, 2009; Simpson et al., n.d.). Our data do not argue against this notion, but raise the additional possibility that DA dysregulation may also contribute to schizophrenia pathogenesis by directly derailing structural development of “higher” associative cortices during childhood and adolescence. This possibility provides a mechanistic bridge between the dopamine hypothesis of schizophrenia and the neurodevelopmental hypothesis of schizophrenia, which sees aberrant early brain development before the onset of illness as being central to the neurobiology of schizophrenia (Rapoport et al., 2005).
