Abstract
SYNGAP1 disorder is a syndromic neurodevelopmental disorder that caused mainly by de novo mutations in the SYNGAP1 gene. People with SYNGAP1 disorder often present with a diverse set of symptoms including autism spectrum disorder (ASD), intellectual disability (ID), epilepsy, gastrointestinal distress, developmental delay, sensory hypersensitivity, high pain thresholds and risk-taking behaviors. To explore the underlying molecular and cellular processes, heterozygous Syngap1 rodent models have been in use for the past two decades. Given their in-utero development, it has been difficult to explore the early developmental processes and perform high-throughput screens in the Syngap1 rodent models. With increasing disorder awareness and prevalence, as an alternate vertebrate model with high fecundities and well-characterized, stereotypic behaviors, we generated Syngap1a and Syngap1b loss-of-function zebrafish models using CRISPR/Cas9 genome editing to further explore functions of Syngap1 in nervous system development and behavior.
Our Syngap1a and Syngap1b loss-of-function models showed reduced Syngap1 expression at both mRNA and protein levels. We identified a zebrafish Syngap1b isoform with a putative PDZ-interacting domain that is similar to the well-studied mammalian Syngap1 α1 isoform that is localized at the excitatory post synapses in the brain. Comparable with the mammalian models, syngap1ab+/- zebrafish larvae showed sensory-induced hyperactivity for both light and acoustic stimulation. Finer analyses of these behavioral data show that Syngap1ab mutant larvae have more frequent movements and move further in a given bout. Our findings further suggest that observed hyperactivity is context-dependent in that mutants are less responsive than wild type to sub-threshold stimuli but more responsive to suprathreshold stimuli. Understanding the Syngap1 genotype/phenotype relationship in this way lays the foundation for future studies of the neural circuits that underlie Syngap1-specific behavioral differences.