CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene Leads to Social Impairments in Zebrafish.

Haploinsufficiency of the gene, encoding a SET domain-containing histone methyltransferase, has been identified as a cause of intellectual disability and Autism Spectrum Disorder (ASD). Recently, the zebrafish has emerged as a valuable model to study neurodevelopmental disorders because of its genetic tractability, robust behavioral traits and amenability to high-throughput drug screening. To model human haploinsufficiency, we generated zebrafish mutants using the CRISPR/Cas9 technology and characterized their morphological, behavioral and molecular phenotypes. According to our observation that is expressed in adult zebrafish brain, including those areas controlling social behavior, we found that heterozygous mutants exhibit defective aggregation and coordination abilities required for shoaling interactions, as well as indifference to social stimuli. Interestingly, impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD individuals. The molecular analysis underscored the downregulation of genes encoding proteins involved in the synaptic structure and function in the adult brain, thus suggesting that brain hypo-connectivity could be responsible for the social impairments of mutant fishes. The zebrafish mutants display ASD-like features and are a promising haploinsufficiency model for drug screening aimed at reversing the behavioral phenotypes.