SU97. Zebrafish Brain Activity Phenotypes Unify Schizophrenia-Associated Genes

Abstract

Background: Large-scale genome-wide association studies have begun to uncover numerous candidate genes linked to schizophrenia. Ye t it remains unclear how these genes function and how they contribute to the underlying molecular, cellular, developmental and behavioral processes disrupted in the disorder. Method(s): Recent technological breakthroughs in zebrafsh-targeted genome editing with CRISPR/Cas9, whole-brain activity imaging, brain atlas registration, behavioral profling-combined with the ease of studying large numbers of animals make it an ideal system for analyzing psychiatric disease genes. Combining these technologies, I have generated zebraf-ish mutants for over 100 schizophrenia-associated genes and am analyzing them for differences in neurological activity and morphology, as well as altered behavior. To assay these mutants for functionally altered brains, I am using a high-throughput antibody staining technique that reports integrated neuronal activity in freely swimming larvae. To determine whether these mutants have altered behavior, I am characterizing their movement rates during the day and night (sleep) and in a stressful heat condition, startle responses to both light changes and sounds, habituation to a stimulus (primitive form of learning), and level of prepulse inhibition. Result(s): I have completed screening of these zebrafsh mutants for altered brain activity and morphology, and over one-third display phenotypes. Comparing brain activity maps between mutants, I have discovered that multiple schizophrenia-associated genes alter activity in the same brain regions. These data have also clarifed ambiguity at multi-gene loci, associated genomic regions containing multiple genes only one of which is likely involved in disease pathology, by identifying the most likely candidate genes through shared phenotypes. Observed brain abnormalities in mutants resemble known schizophrenia patient phenotypes, such as the loss of GABAergic inhibitory neurons and altered activity in olfactory and visual sensory systems. Behavioral abnormalities observed in mutant animals are also reminiscent of motor behaviors observed in patients. Conclusion(s): The fnding of shared phenotypes suggests that seemingly unrelated schizophrenia-associated genes may be involved in common underlying pathways. Our work illustrates how studies in a simple animal model nervous system can help uncover these pathways and elucidate gene function. 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.This work was supported by Harvard University, NIH research grants to Alexander Schier, and a Damon Runyon Cancer Research Foundation postdoctoral fellowship to Summer Thyme.