The Study On GPR50 Function In Autism Spectrum Disorder

Autism spectrum disorder(ASD)is a complex neuron developmental disorder characterized by a broad spectrum of clinical manifestations,including qualitative impairments in verbal and nonverbal communication,qualitative impairments in reciprocal social interactions,and restricted repetitive and stereotyped patterns of behavior,interests and activities.G protein-coupled receptor 50(GPR50)is an X-linked orphan G protein-coupled receptor,which is also known as melatonin-related receptor.GPR50 is expressed in the hypothalamus,pituitary and hippocampus of adult mammalian brain.Studies indicates that GPR50 is associated with bipolar affective disorder(BPAD),major depressive disorder(MDD)and schizophrenia.These lines of evidence suggest a potential role of GPR50 in brain development.More importantly,GPR50 has two variations,D502-505 and T532A,in male ASD patients,suggesting a strong correlation between ASD and GPR50.However,the function of GPR50 in the brain remains unclear.In this project,we used male GPR50 knockout mouse(GPR50-/Y)to explore the role of GPR50 in the etiology of ASD.Our data indicate GPR50-/Y mice exhibit autism-like behaviors including impaired social interaction,stereotyped behavior and defective cognition.We further observe enhanced proliferation of neural progenitor cells(NPCs)and increases numbers of astrocytes in the hippocampus of adult GPR50-/Y mice.Whereas the density of neurons in the hippocampus CA1 areas and dendrite spine in the DG area exhibit decline in adult GPR50-/Y mice.Moreover,we show that deficiency of GPR50 results in increased apoptosis and the levels of reactive oxygen species(ROS),which is accompanied by increased levels of mitochondrial protein.These results suggest that GPR50 deficiency leads to mitochondrial dysfunction.Therefore,we identify in the present project GPR50 is an important factor in maintaining the physiological function of nervous system during development.Deficiency of GPR50 results in enhanced proliferation of NPCs and density of astrocytes,whereas reduced density of neurons in the CA1 and of dendrite spines in the DG in the hippocampus,which is accompanied by autism-like behavior in the male mouse.This histological and behavioral abnormality upon GPR50 deficiency may link to mitochondrial dysfunction.