Many of the recently discovered schizophrenia candidate genes [e.g., COMT, GRM3, PPP3CC (calcineurin), DARPP32] have been associated with cognitive dysfunction, a symptom relatively resistant to current antipsychotic treatments and viewed as a core symptom of schizophrenia. The genetic animal models with mutations in the genes involved in brain development (e.g., DISC1, NRG1, DTNBP1) have provided insights into molecular mechanisms of abnormal neurodevelopment in schizophrenia. In particular, several recent studies on disruptions of the DISC1 gene in mice illustrate the great potential of the new genetic approaches but also signal the vast complexity of the problem.
The initial rationale for studying the effects
of mutations in DISC1 came from the discovery of the chromosomal translocation resulting in a breakpoint in the DISC1 gene that co-segregated with major mental illness in a Scottish family (reviewed by Porteous et al. 2006). These clinical findings were followed by a number of association studies, which reported that numerous single nucleotide polymorphisms (SNPs) across the gene were associated with schizophrenia and mood disorders and a variety of intermediate phenotypes, including hippocampal function and structure, prefrontal gray matter volume, memory and cognition, suggesting that other problems in the DISC1 gene may exist in other subjects/populations.
Animal models constructed to mimic partial loss of DISC1 function suggested that DISC1 is necessary to support development of the cerebral cortex as its loss resulted in impaired neurite outgrowth and the spectrum of behavioral abnormalities characteristic of major mental disorders (Kamiya et al. 2005; Koike et al. 2006; Clapcote et al. 2007; Hikida et al. 2007). Unexpectedly, however, another DISC1 knockdown model, achieved by RNA interference in single cells of the dentate gyrus, has recently demonstrated that DISC1 may also function as
a brake on neuronal development, and that its loss could lead to the opposite effects: dendritic overgrowth and accelerated synapse formation and maturation of newly generated neurons (Duan et al. 2007). Other emerging studies continue to reveal the highly complex nature of the DISC1 gene with multiple isoforms exhibiting different functions, perhaps depending on localization, timing and interactions with
a multitude of other gene products, some of which appear to confer susceptibility to mental illness in their own right, independently of DISC1 (Hennah et al. 2007; Hodgkinson et al. 2007; Kakiuchi
et al. 2007; Lipska et al. 2006; Millar et al. 2005; Pickard et al. 2007). Similar molecular complexity has also emerged in other susceptibility genes for schizophrenia, GRM3 (Sartorius et al. 2006), NRG1 (Tan et al. 2007) and COMT (Tunbridge et al. 2007). With the growing knowledge of transcript complexity, it becomes increasingly clear that subtle disturbances of isoform(s) of susceptibility gene products and intricate interactions between the susceptibility genes may account for the etiology of neuropsychiatric disorders. Research in animals will have a critical role in disentangling this web of interwoven genetic pathways.
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