Schizophrenia is the most debilitating mental illness and its onset is in young adulthood. Its incidence, about 1% of the population, is the same as diabetes. However, the pathogenesis of schizophrenia is still unclear, entirely hampering the development of therapeutic strategies. Recent advances in neuroscience suggest that schizophrenia is a brain disorder stemming from a subtle change in neurodevelopment, resulting in a robust disturbance of some neurotransmission systems many years later.
It is known that genetic predisposition in the etiology of schizophrenia exists. However, even though several genes have been associated with schizophrenia, most of the functions of the gene products remain to be elucidated. Furthermore, it is still unclear how these gene products are functionally linked together towards the pathogenesis and pathophysiology of schizophrenia.
We are exploring functional crosstalks of the disease gene products, trying to build a unified model for schizophrenia that accounts for disturbances of neurodevelopment and neurotransmission.
Recent progress in human genetics also suggests, although their clinical manifestations and course are substantially distinct, schizophrenia and mood disorders share common genetic factors. Therefore, we hope that our progress in research for schizophrenia may also be applied for the better understanding in the pathogenesis and pathophysiology of mood disorders, such as bipolar disorder and major depression.
Figure 1. Knocked down expression of DISC1 by RNA interference leads to disturbed cortical development, especially in dendritic arborizaztion of pyramidal neurons. | | Involvement of neurodevelopmental deficits in schizophrenia has been suggested by epidemiological studies, neuropathology, and brain imaging. A recent study of ours on a promising risk gene for schizophrenia, DISC1, indicates that schizophrenia-associated mutations in this gene lead to disturbance of proper development in cerebral cortex. We are interested in how DISC1 and other risk gene products, together with environmental factors, including viral infections, functionally interact with each other, especially in neuronal migration, dendritic arborization, and synaptic maturations, to form basic risks for schizophrenia.
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Figure 2. Association of schizophrenia with genes that encodes proteins involved in synthesis and degradation of D-serine, an agonist of the NMDA glutamate receptor. | | Evidence from both genetic and clinico-pharmacological studies suggests that disturbance of glutamatergic neurotransmission, especially D-serine/NMDA receptor-mediated signaling, plays a role in the pathophysiology of schizophrenia. We have two focuses in addressing this question: (1) disturbance of biosynthesis and degradation of D-serine; (2) disturbance of D-serine/NMDA receptor-mediated synaptic reorganization together with ErbB4/neuregulin-1, DISC1, and their associated proteins. In biochemical and cellular approaches, we are building working hypotheses to be tested in animal models, and further confirmed in studies with human tissues.
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Figure 3. (Click Figure to Enlarge) We take a multifaceted approach based on promising molecular leads, such as DISC1, which include genetic analyses, molecular/cellular biology, and generation/characterization of genetically-engineered mice. We arrange our research program so as to link such basic information to clinical conditions and vis versa, trying to establish a unified model for schizophrenia and mood disorders. | | In addition to classic animal models for schizophrenia (drug-induced models, brain-lesion models), we are establishing and characterizing genetically-engineered mice for schizophrenia susceptibility genes, including neuregulin-1, ErbB4, nNOS, PICK1, and DISC1. The majority of these genes also confer risk for mood disorders. These mice allow us to study how variation in genetic factors lead to subtle defects during neurodevelopment that result in robust phenotypic changes after puberty associated with the disturbance of glutamate and dopamine neurotransmission. We are also studying the impacts of environmental factors, especially infection of cytomegalovirus during developmental stages, on the genetic risk in the pathophysiology of schizophrenia. Altogether, we are trying to build a unified model for schizophrenia that accounts for disturbances of neurodevelopment and neurotransmission. We expect this model to also assist in helping us understand other mood disorders.
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K. Fujii, K. Maeda, T. Hikida, A.K. Mustafa, R. Balkissoon, J. Xia, T.Yamada, Y. Ozeki, R. Kawahara, M. Okawa, R.L. Huganir, H. Ujike, S. H. Snyder and A. Sawa Serine racemase binds PICK1: potential relevance to schizophrenia. Mol. Psychiatry. 11(2); 150-157 (2006)
A. Kamiya, K. Kubo, T. Tomoda, M. Takaki, R. Youn, Y. Ozeki, N. Sawamura, U. Park, C Kudo, M. Okawa, C.A. Ross, M.E. Hatten, K. Nakajima, A. Sawa A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nature Cell Biol., 7; 1167-78 (2005)
A. Sawa, S.H. Snyder Genetics. Two genes link two distinct psychoses. Science; 310; 1128-9 (2005)
A. Sawa, S.H. Snyder Schizophrenia: diverse approaches to a complex disease. Science, 296; 692-695 (2002)
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