Prospective Studies of the Pathogenesis of Schizophrenia

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DESCRIPTION (provided by applicant): The proposed UNC-CCNMD is a multidisciplinary organization comprised of scientists from the University of North Carolina, Duke, Harvard and the University of Washington directed by Dr. Jeffrey Lieberman, a research psychiatrist whose career has focused on the natural history and neurobiology of schizophrenia. The proposed center consists of 3 projects and 2 cores. The general aim of the UNC-CCNMD is to identify predictors of onset of schizophrenia and the underlying pathology in neurodevelopmental mechanisms that mediate disease vulnerability and expression. Although schizophrenia is believed to be a genetically mediated neurodevelopmental disorder, there is little clinical research demonstrating early abnormalities in brain structure and function and no definitive data identifying risk genes. Moreover, studies have neither identified causal neurobiologic mechanisms nor linked them to the natural history and clinical onset of the disease. Symptoms of schizophrenia emerge predominantly between the ages of 15 and 25 years. Thus, neurodevelopmental events in adolescence may be targets of pathogenic processes that contribute to disease vulnerability and expression. We hypothesize that schizophrenia vulnerability and expression arises from the consequences of dysconnectivity in thalamo-limbic-cortical circuits (TLC) due to disrupted differentiation of cortical GABA neurons and the cellular elements with which they modulate local cortical circuitry. These developmental anomalies in GABA interneurons confer vulnerability that when acted on by ontogenetic and environmental events during adolescence trigger dysfunction in TLC circuits and disease expression. 2 clinical and 2 preclinical projects will address this hypothesis. The clinical projects are prospective longitudinal studies of 2 unique high-risk populations enriched for the development of schizophrenia: adolescents and young adults with prodromal signs (Project 1) and fetuses and neonates of parents with schizophrenia (Project 2). The preclinical project involves a study of cell biological mechanisms of dendritic and axonal development in cortical GABA neurons as well as consequences of mutations in suspected vulnerability genes on this process (Project 3). Thus, the UNC-CCNMD is distinguished by its focus on behavioral and neurobiologic mechanisms that lead to the onset of the disease rather than clinical or pathologic correlates that emerge once it has been diagnosed. Our results will contribute to the identification of diagnostic methods and novel targets for intervention prior to the clinical deterioration that characterizes schizophrenia. In this way the Center will not only advance the neuroscience of schizophrenia but will have an immediate impact on the clinical care and treatment of persons who have and are at risk for schizophrenia.