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Background    DYRK1A  maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing  Dyrk1a  which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link  Dyrk1a  dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo  dyrk1aa  KO model using zebrafish.    Methods  We identified a patient with a mutation in the  DYRK1A  gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a  dyrk1aa  KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of  dyrk1aa  KO zebrafish through in situ hybridization with various probes including  c-fos  and  crh  which are the molecular markers for stress response.    Results  Microarray detected an intragenic microdeletion of  DYRK1A  in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior,  dyrk1aa  KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in  dyrk1aa  KO zebrafish was further confirmed by molecular analysis of  c-fos  and  crh  expression. Transcriptional expression of  c-fos  and  crh  was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context.    Conclusions  In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of  DYRK1A  as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes.    Electronic supplementary material  The online version of this article (10.1186/s13229-017-0168-2) contains supplementary material, which is available to authorized users.

Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism