Implications for mental disorders.
disc1 was initially identified as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression in a large Scottish family ([Blackwood et al., 2001] and [Millar et al., 2000]). Genetic linkage and association studies have suggested that disc1 may be a general risk factor for schizophrenia and some other mental disorders, such as bipolar disorder and depression ([Harrison and Weinberger, 2005], [Ishizuka et al., 2006] and [Mackie et al., 2007]). The relevance of disc1 to schizophrenia was further demonstrated by a functional correlation between genetic variations of disc1 in humans and specific defects in hippocampal structures and functions (Callicott et al., 2005). In rodent models, one study with an endogenous mutant disc1 identified in the 129S6/SvEv mice supports a role of DISC1 in modulating working memory (Koike et al., 2006). A recent study showed that mice with a missense mutation (Q31L) exhibit deficits in the force swim test and depression-like behaviors, while L100P mutant mice exhibit schizophrenia-like phenotypes, such as defects in prepulse inhibition and latent inhibition (Clapcote et al., 2007). Whether defects in adult neurogenesis contribute to psychological disorders with adult onsets, such as schizophrenia, bipolar disorder, and major depression, remains unknown and is an interesting topic for future investigation. Interestingly, a recent study suggests that cell proliferation in the adult human dentate gyrus is decreased in schizophrenia, but not in depression (Reif et al., 2006). Emerging evidence also suggests that many mental disorders are developmental in nature and may result from defects in neuronal integration ([Arnold et al., 2005], Lewis and Levitt, 2002 D.A. Lewis and P. Levitt, Schizophrenia as a disorder of neurodevelopment, Annu. Rev. Neurosci. 25 (2002), pp. 409–432. View Record in Scopus | Cited By in Scopus (297)[Lewis and Levitt, 2002] and [Zoghbi, 2003]). Our identification of DISC1 as a critical regulator controlling sequential steps of neuronal integration raises the possibility that DISC1 may be a key molecular player in the etiology of major mental illness.
