The Role And Mechanism Of Autism High Risk Gene TBR1 In Neurodevelopment And Behavior Of Zebrafish

Autism spectrum disorders?ASDs?is a common neurodevelopmental disorder whose core features include defects in social interaction and communication,repetitive behaviors and cognitive disorder.There is no effective drug and method for the core symptoms improvement so far,mainly due to the lack of comprehension of autism pathogenesis,thus systematic research is urgent.Zebrafish is a new model animal which is widely used in developmental biology research and which plays an increasingly important role in study of human diseases.The nervous system of zebrafish is relatively simple,but the behaviors can be advanced such as social interaction,even though there is little research on zebrafish for autism.The causes of autism spectrum disorders are complex,and genetic mutation is an important pathogenic factor.More than 100 risk genes of ASDs have been identified.TBR1 as a high risk gene,whose mutant in mice led to abnormal brain development and behavioral disorders,was conservative among species.In this study,we explored the autism with tbr1 mutant zebrafish.We found tbr1 specially expressed in zebrafish telencephalon,either tbr1b^-/-larval or adult zebrafish showed abnormal behaviors such as social disorder,which is similar to some behavioral representations of autistic human.Further studies have found abnormal differentiation on glutamatergic neurons in zebrafish,which might affect the excitatory and inhibitory balance of the nervous system,and thus exhibited behavioral abnormalities.After treated tbr1b^-/-zebrafish with glutamatergic agonist D-cycloserine,we found the abnormal behaviors of mutation zebrafish has significantly improved,suggested glutamatergic neurons may be an important factor of social dysfunction.We also found structural abnormality in anterior commissure?AC?of the telencephalic dorsorostral cluster?DRC?neurons in zebrafish,which couldn't form normal connections.In addition,there was an abnormity of supra-optic tract?SOT?.These anomalies might also a cause of behavior abnormalities.Our study discussed the behavior changes in tbr1b^-/-zebrafish,revealed the abnormal glutamatergic neurons and the abnormal connection of AC may affect zebrafish behaviors.A disease model was established for the further study of pathogenesis of autism.Drug intervention can improve the behavior of zebrafish,so as to contribute to high–throughput drugs with zebrafish model.