The Function And Mechanism Of Serotonin And Its Receptors In Drosophila Social Behavior

Autism spectrum disorder（ASD）is a neurodevelopmental disorder characterized by impairments in social interaction and repetitive stereotyped behaviors.The incidence rate of ASD kept increasing during the past years,which brought a great burden to the family and society.ASD is highly clinically heterogeneous and the pathophysiology of autism is complicated,genetic and environmental factors are both involved in the ASD.Monoamine neurotransmitters,especially serotonin,have been proven to be associated with ASD.Hyperserotonemia was found in ASD patients and has been a biomarker of the ASD.However,so far,most of the studies have been focused on the transportation and reuptake of the serotonin,the association between the serotonin receptors and ASD pathophysiology remains to be fully elucidated.Serotonin is a very important neurotransmitter controlling multiple behaviors,and previous studies showed that serotonin can regulate different behaviors through different receptors in different brain regions.To investigate the functions and mechanisms of different serotonin receptors in abnormal behaviors of ASD,we generated the knock-out mutants of the five serotonin receptors with the help of CRISPR/Cas9 in Drosophila,and investigated their social impairment by social space analysis and grooming analysis.Firstly,we found that the serotonin synthesis mutant Trh⁰¹ showed a significantly larger distance to its closest neighbor and more grooming episodes compared to the control,which verified the effect of serotonin on social space and repetitive behavior of Drosophila and the feasibility of these two behavior assays in Drosophila.Secondly,we perfomed the same behavior assay in the serotonin receptors knock-out mutant flies,and found that only the 5-HT2B knock-out homozygous mutants showed social aggregation and less grooming numbers,while the mutants of other receptors are not affected.The aberrant social space and grooming numbers were also observed in 5-HT2B knock down homozygous mutant flies,which suggests that serotonin regulates the social space and number of grooming episodes by 5-HT2B receptors in Drosophila.Finally,we found that knockdown 5-HT2B specifically in mushroom bodies could induce abnormal social space,which indicates the importance of mushroom body in regulating the social interaction.These results reveal the role of 5-HT2B as a main receptor that receive the serotonin signal to regulate the ASD-related social behavior,which might provide some insights in diagnosis and treatment of ASD.