To Explore The Role Of Gm527 In The Pathogenesis Of Schizophrenia

Background:Schizophrenia is a serious mental illness.Its etiology and pathogenesis have not been clarified yet.Clinical diagnosis is mainly based on medical history and mental state.Studies have found excessive release of dopamine neurotransmitters is associated with the development of positive symptoms（such as delusions and hallucinations）,and dopamine D₂receptor antagonists can effectively treat positive symptoms of schizophrenia.Imaging studies have shown hippocampal hyperactivity,the volume of hippocampal CA1 in schizophrenic patients is significantly reduced and the shape is deformed,and these structural changes of CA1 are related to positive symptoms.In addition,genetic factors also play an important role in the onset of schizophrenia,genome-wide association study has identified hundreds of schizophrenia-related risk genes,including C14orf28,which is called Gm527 in mice.Gm527 protein is a dopamine receptor-interacting protein,and its function is largely unknown yet.Therefore,here we will investigate the function of Gm527 and the mechanism how Gm527 is involved in schizophrenia phenotypes.Objective:To explore the role of Gm527 in the pathogenesis of schizophrenia.Methods:The Cre-expressing virus was injected into the hippocampal CA1 of 8-week-old Gm527^loxp/loxp mice to conditionally knock out Gm527 in neurons.The Co-immunoprecipitation was used to determine whether Gm527 and dopamine D₂ receptor bind to each other.DRD2-Cre mice were crossed with Gm527^loxp/loxp mice to generate D₂-Gm527^-/-mice,in which Gm527 was ablated in D₂receptor-positive neurons.Hyper-locomotion activity,sensory motor gating,working memory,and long term memory was detected through open field test,pre-pulse inhibition,8-arm maze test,and fear conditioning respectively.8-10-week-old D₂-Gm527^-/-mice were stained with neonatal neurons in the dentate gyrus to detect adult neurogenesis.Results:（1）Knocking out Gm527 in neurons of hippocampal CA1 could induce schizophrenia-like behavioral phenotypes in mice.（2）Co-immunoprecipitation showed Gm527 could bind with dopamine D₂ receptor.（3）Knocking out Gm527 in the D₂receptor-positive neurons could also induce schizophrenia-like behavioral phenotypes in mice and inhibit the dentate gyrus adult neurogenesis.Conclusion:Knock out Gm527 in neurons of hippocampal CA1 and D₂ receptor-positive neurons can induce schizophrenia-like behavioral phenotypes in mice,suggesting the important role of Gm527 in the pathogenesis of schizophrenia.In addition,we also found that knock out Gm527 in D₂-receptor-positive neurons affects adult neurogenesis,suggesting Gm527 might induce schizophrenia-like phenotypes through impairment of adult neurogenesis.