Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication and restrictive, repetitive behaviors. ASD is considered one of the most heritable of neuropsychiatric disorders. Whole-exome sequencing has led to a growing list of genes that are strongly associated with ASD through the identification of an increased rate of de novo loss of function mutations in these genes in affected individuals. However, we are in need of model systems to identify common neurodevelopmental mechanisms that are affected by risk gene disruption. To address this, we are capitalizing on the advantages of zebrafish as a model system to investigate how disrupting these risk genes affects brain development and simple behaviors. First, we generated loss of function mutations in the zebrafish orthologs of nine ASD risk genes using CRISPR/Cas9 technology. These genes include: CHD8, SCN2A, POGZ, TBR1, GRIN2B, DYRK1A, KATNAL2, CUL3, and ANK2. For genes that are duplicated in zebrafish, we generated double mutant lines. Next, we are utilizing high-throughput behavioral analysis and high-resolution brain imaging to assess how disruption of these genes affects simple behavioral phenotypes and the development of excitatory and inhibitory neuronal populations. We are beginning to identify unique pharmaco-behavioral phenotypes among mutant lines. Next, our goal is to compare the behavioral profiles across mutant lines to identify pharmacological suppressors of abnormal behavioral fingerprints in mutants. Together, these studies have the potential to identify pharmacological pathways with relevance to ASD.