Generation of etiological models for schizophrenia by chromosome engineering

Mclean Hospital, Belmont MA

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Abstract

DESCRIPTION (provided by applicant): The relevance of copy number variations (CNVs), i.e. deletions and duplications in psychiatric disorders has recently been discovered. Large-scale genome surveys show an association between deletions on chromosomes 1q21.1 and 15q13.3 and schizophrenia with odds ratios of 7 to 18. We now propose generating two preclinical etiological models of schizophrenia using chromosome engineering to model these hemizygous deletions in murine embryonic stem cells and live animals. Mice carrying hemizygous deletions corresponding to those found in schizophrenic patients will undergo an initial behavioral characterization with an emphasis on examining sensorimotor gating and working memory deficits and are expected to be valuable tools for investigating the phenotypic potential of strong risk factors of schizophrenia and in particular the biological mechanisms underlying this increased risk. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe mental disorder affecting approximately 1% percent of the population worldwide but our knowledge about the pathogenesis of the disease is critically limited. Based on human large-scale genome-wide surveys identifying an association between specific copy number variations on chromosomes 1q21.1 and 15q13.3 and schizophrenia, we will generate two novel etiological models of schizophrenia using chromosome engineering modeling these hemizygous deletions in mice. Examination of these mice will be important for increasing our understanding of the pathogenesis and pathophysiology of the disease and for the development of novel treatment strategies.