Functional Analysis of Schizophrenia-Associated Genes

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PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate the functions of schizophrenia-associated genes using zebrafish as a model system. Large-scale genome-wide association studies have begun to uncover numerous candidate genes linked to schizophrenia. Yet it remains unclear how these genes function and how they contribute to the underlying molecular, cellular, developmental and behavioral processes disrupted in the disorder. Recent technological breakthroughs in zebrafish – targeted genome editing, whole-brain activity imaging, brain atlas registration, behavioral profiling – combined with the ease of studying large numbers of animals make it an ideal system for analyzing psychiatric disease genes. Preliminary studies led to the creation of zebrafish mutants for 96 schizophrenia-associated genes. Characterization of 59 of these mutants for altered brain anatomy and activity has revealed 27 mutants with phenotypical abnormalities. In particular, ZNF536, a schizophrenia-associated transcription factor, was found to be involved in the development of GABAergic inhibitory neurons in the forebrain and cerebellum as well as regulate locomotion. During the K99 phase, this project will complete the analysis of mutant brain anatomy. In addition, all mutants will be tested for behavioral abnormalities, including motor behaviors associated with schizophrenia, such as defective prepulse inhibition (Aim 1). In parallel, the developmental roles of ZNF536 will be studied to test the hypothesis that this transcription factor is responsible for the development of GABAergic neurons, and that its loss results in the de-inhibition of downstream circuits. To define the molecular mechanisms by which ZNF536 exerts its effects, ZNF536 target genes will be isolated (Aim 2). Similar in-depth characterization of other interesting genes will be undertaken in the R00 phase to discover additional pathways regulated by schizophrenia-associated genes. Understanding the molecular, cellular, developmental and behavioral processes regulated by schizophrenia- associated genes will provide the foundation to understand the causes of schizophrenia and develop new diagnostics and therapies.