Meixin Hu

Vision is fundamental to the acquisition of motor, cognitive, and social skills, playing a crucial role in typical development. Early visual impairments are associated with various neurodevelopmental conditions, including Autism Spectrum Disorder (ASD). The (Brain-specific serine/threonine-protein kinase 2, BRSK2) gene has been identified as a high-risk gene for ASD. This study aims to investigate the role of brsk2 in retinal photoreceptor development and visual function in zebrafish. Using behavioral assays, histological analysis, and transcriptomic profiling, we assessed the impact of brsk2 deletion on retinal structure and function. The results showed that brsk2ab^−/− zebrafish larvae exhibited significantly enhanced light perception compared to wild-type (WT) controls. Structural analysis of the retina revealed disruptions in the layered organization, along with up-regulated rhodopsin expression in retinal cells. Additionally, transcriptomic analysis indicated that key opsins and genes involved in visual development and phototransduction pathways were markedly up-regulated following brsk2 deletion. This research highlights the importance of brsk2 in early retinal circuit development and its potential implications for understanding sensory processing deficits in neurodevelopmental disorders. By linking BRSK2 to specific sensory phenotypes, this study addresses a critical gap in knowledge regarding the mechanisms underlying sensory abnormalities in ASD and related conditions.

Both social and motor development play an essential role in an individual’s physical, psychological, and social well-being. It is essential to conduct a dynamic analysis at multiple time points during the developmental process as it helps us better understand and evaluate the trajectory and changes in individual development. Recently, some studies found that mutations in the BRSK2 gene may contribute to motor impairments, delays in achieving motor milestones, and deficits in social behavior and communication skills in patients. However, little is known about the dynamic analysis of social and motor development at multiple time points during the development of the brsk2 gene. We generated a novel brsk2-deficient (brsk2ab^−/−) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including that of locomotor behaviors, social behaviors, and anxiety behaviors from the larval to adult stages of development. Compared to wild-type zebrafish, brsk2ab^−/− zebrafish exhibited a catch-up growth pattern of body length and gradually improved locomotor activities during the developmental process. In contrast, multimodal behavior tests showed that the brsk2ab^−/− zebrafish displayed escalating social deficiency and anxiety-like behaviors over time. We reported for the first time that the brsk2 gene had dynamic regulatory effects on motor and social development. It helps us understand developmental trends, capture changes, facilitate early interventions, and provide personalized support and development opportunities for individuals.

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 novo SHANK2 mutations 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 shank2b-deficient zebrafish model (shank2b^−/−). The adult shank2b^−/− zebrafish 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 in shank2b^−/− zebrafish, 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.