Behavioral and Sensory Deficits Associated with Dysfunction of GABAergic System in a Novel-Deficient Zebrafish Model.

Abstract

Hyper-reactivity to sensory inputs is a common and debilitating symptom of autism spectrum disorder (ASD), but the underlying neural abnormalities remain unclear. Two of three patients in our clinical cohort screen harboring de novomutations also exhibited high sensitivity to visual, auditory, and tactile stimuli, so we examined whether shank2 deficiencies contribute to sensory abnormalities and other ASD-like phenotypes by generating a stable-deficient zebrafish model (). The adultzebrafish demonstrated reduced social preference and kin preference as well as enhanced behavioral stereotypy, while larvae exhibited hyper-sensitivity to auditory noise and abnormal hyperactivity during dark-to-light transitions. This model thus recapitulated the core developmental and behavioral phenotypes of many previous genetic ASD models. Expression levels of γ-aminobutyric acid (GABA) receptor subunit mRNAs and proteins were also reduced inzebrafish, and these animals exhibited greater sensitivity to drug-induced seizures. Our results suggest that GABAergic dysfunction is a major contributor to the sensory hyper-reactivity in ASD, and they underscore the need for interventions that target sensory-processing disruptions during early neural development to prevent disease progression.