The Role And Mechanism Of Autism Risk Gene CHD8 In Neuron Differentiation And Behavior Of Zebrafish

Autism spectrum disorder is a broad range of pervasive neurodevelopmental disorder characterized by challenges with social interaction and communication,repetitive behavior or narrow,obsessive interests.No diagnostic biomarker or therapeutic drug or curing method is available yet.Autism is highly heritable and many risk genes have been identified,including CHD8.Clinical findings showed that the autism patients with CHD8 disruptions display a high rate of macrocephaly,which might be caused by excessive neurogenesis.It has been reported that chd8 knockdown in zebrafish exhibits the phenotype of macrocephaly.However,the effect of knocking down does not last long,and the diagnostic criteria for autism by behavioral characteristics,therefore,it is imperative to use gene knockout to build an autism model.In this study,CRISPR/Cas9 was used to knock out chd8 zebrafish for experiments.In the early stage of development,it was found that homozygotes have macrocephaly and abnormal neuron increase.Further studies have found that the balance disorders of excitation and inhibition(E/I balance),based on neurotransmitters such as glutamate,GABA,and glycine.Adult chd8 homozygotes showed abnormal behaviors,such as difficulties with social interaction and communication.Based on the above findings,we propose that the mutation of chd8 might disrupt the proliferation and differentiation of neurons,disturbs the balance of excitation and inhibition in the early stage of development,lead to the autism-like behavior of adult zebrafish.