Schizophrenia is a devastating psychiatric illness arising in part from subtle defects in brain development. The Disrupted-ln-Schizophrenia-1 (DISC1) gene is an example of a strong candidate gene for studying the pathogenesis of schizophrenia and associated mental conditions with neurodevelopmental origin. A balanced translocation that segregates in a large Scottish pedigree with schizophrenia and other major mental illnesses causes a deletion of the DlSC1 gene, resulting in a truncated protein product that affects neurodevelopment. Despite of development of several DISC1 mouse models, the key questions regarding the timing of the prenatal vs. postnatal or lasting vs. reversible effects of mutant human (hDISC1) remained unanswered. We propose to identify the time windows of the effects of mutant hDISC1 by using our transgenic mouse model of inducible expression of mutant hDISC1 in forebrain areas. We hypothesize that the nature and magnitude of neuronal effects of mutant hDISC1 will depend on the time of expression of mutant hDISC1 during brain development, with more profound abnormalities resulting from expression during early gestation stages, compared to more subtle alterations resulting from expression during postnatal period and/or adulthood.
Specific Aim 1 will perform quantitative analyses of the volumes of the lateral ventricles, cortex and hippocampus, dendrite arborization and spine density in pyramidal neurons of hippocampus and granule cells of the dentate gyrus of hippocampus as well as adult neurogenesis in the dentate gyrus of hippocampus.
Specific Aim 2 will evaluate the time course of alterations in levels and distribution of endogenous Disc1 and Its interacting proteins, Lis1 and Ndel1, in hDISC1 transgenic mice. Significance: The application is anticipated to advance our understanding of when, where and how mutant DISC1 affects neurodevelopment with relevance to the pathogenesis of schizophrenia and mood disorders. Major mental illnesses have been suggested to arise in part from subtle defects in brain development, particularly development of the cerebral cortex, hippocampus and other forebrain structures (Weinberger, 1996;Lewis, 2002;Eastwood, 2004;Arnold, 2005). The concept of a neurodevelopmental origin of psychiatric diseases has received wide acceptance, although the evidence so far has been primarily indirect (Marenco, 2000). Until very recently an analysis of the pathogenic mechanisms has been impeded by a difficulty in identifying clear mutations in most candidate genes (Millar, 2004;Mackie, 2007). Recent studies of the Disrupted-In-Schizophrenia 1 (DISC1) gene indicate that It can be used as a model for studying aspects of schizophrenia and mood disorders (Ross, 2006;Porteous, 2006). We have demonstrated that expression of mutant human DISC1 (hDISC1) in forebrain neurons of transgenic mice leads to attenuated neurite outgrowth in primary neurons, mild enlargement of the lateral ventricles and selective behavioral alterations similar to some features of schizophrenia and related disorders (Ross, 2006;Pletnikov, 2008). We have shown that the effects of mutant hDISC1 may be mediated via its binding to endogenous mouse Disc1 and alterations in cellular distribution and/or decreased levels of endogenous Disc1 and Lis1, a DISC1 interacting protein involved in neurodevelopment (Gupta, 2002). These findings have suggested dominant-negative mechanisms of the mutant DISC1 effects (Pletnikov, 2007, 2008). Similar results have been demonstrated in transgenic mouse models with constitutive expression of mutant hDISC1, truncated mouse Disc1 or Inducible postnatal expression of a C-terminal fragment of the gene (Hikida, 2007;U, 2007;Shen, 2008). As the deleted C-terminal fragment is not a direct analog of a known variation of DISC1 in humans and can be expressed for a brief period of time during postnatal period only, key questions regarding effects of prenatal vs. postnatal expression or effects of short vs. long-lasting expression or effects of reversible expression cannot be addressed with the above models. We propose to use our model of inducible expression of mutant hDISC1 based on the Tet-off system to identify the time windows for the neurobehavioral effects of mutant hDISC1 and the underlying molecular mechanisms of those effects. This approach is expected to give valuable insights into the molecular underpinning of abnormal brain and behavior development to contribute to mental diseases and will shed more light on the critical time windows for schizophrenia and mood disorders. We hypothesize that the nature and magnitude of molecular and neuronal effects of mutant hDISC1 will depend on the time of expression of mutant hDISC1 during brain development. We predict that early effects of mutant DISC1 may lead to more profound neurodevelopmental abnormalities, whereas early or late postnatal effects of the protein could produce more subtle brain deficits. We hypothesize that mutant hDISC1 affects neurodevelopment via dominant-negative mechanisms by altering the functions of endogenous mouse Dics1, Lis1, and Ndel1.
The grant application proposes to characterize brain and behavior development in transgenic mice that bear a mutant human gene, Disrupted-In-Schizophrenia 1 (DISC1), associated with schizophrenia and related psychiatric disorders. The study will identify the critical time windows when expression of the mutant gene is particularly detrimental to normal brain development. The proposal will advance our understanding of the mechanisms whereby the mutant gene affects normal neurodevelopment relevant to serious psychiatric diseases and will facilitate use of this new model for pre-clinical therapeutic trials.
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