Functional study of mental disorder genes
We are conducting a systematic zebrafish knockout project to validate candidate genes for mental disorders, including autism. Knockout (KO) zebrafish for the Miles-Carpenter syndrome gene (ZC4H2) were created and KO animal exhibited abnormal swimming, defective eye movement and pectoral fin contractures. We observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord. Loss of function of ZC4H2 thus likely results in altered connectivity of neuronal circuits, infantile spasm and intellectual disability. The second case is related to autism spectrum disorders (ASDs). ASDs comprise a wide range of neurodevelopmental disorders, characterized by deficits in social behavior, along with repetitive behaviors and impaired communication. Though the exact causes for ASD remain poorly understood, genetic mutations resulting in altered gene function have been implicated causally in ASD. Intragenic mutations in DYRK1A, which have been shown previously to be associated with clinical aspects of Down syndrome, have been associated recently with microcephaly and ASD-like symptoms. We provide a case study of an individual with a 21kb microdeletion within the DYRK1A locus, who has both microcephaly and ASD. We show that dyrk1aa KO fish have microcephaly and impaired social interactions through two newly developed behavioral tests: social interaction and shoaling assays. Also, we confirmed that behavior analysis for ASD through our dyrk1aa KO zebrafish is experimentally tractable, and propose these social behavioral assay methods in zebrafish as a tool for the widespread study of ASD candidate genes.