【摘 要】
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Objective Irreversible abnormalities during brain development are thought to cause neurodevelopmental disorders such as schizophrenia.Developmental processes, such as cell migration and differentiatio
【机 构】
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Key Lab Genet Dev & Neuropsychiatry Disorders, Shanghai Jiao Tong University, BIO X Center Shanghai
【出 处】
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中国神经科学学会第九届全国学术会议暨第五届会员代表大会
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Objective Irreversible abnormalities during brain development are thought to cause neurodevelopmental disorders such as schizophrenia.Developmental processes, such as cell migration and differentiation, continue in restricted brain regions of adults, including neurogenesis in the subgranular zone of the dentate gyrus (DG).To test the role of these adult developmental processes in phenotypes associated with schizophrenia, we specifically disrupted the expression of DISC1, an important susceptibility gene for schizophrenia, in DG newborn neurons in the adult brain.The present study is to explore whether DISC1 knockdown in DG adult-born neurons caused behavioral and cognitive deficits associated with psychiatric disorders.Methods High titers of oncoretroviruses engineered to knock-down DISC1 with an shRNA approach was stereotaxically injected into the dentate gyrus of mice.Two weeks after surgery, Morris water maze, object-place recognition task, elevated plus maze and forced swimming were carried out.Results (1) DISC1 regulates morphogenesis and axonal targeting of adult-born dentate gyrus neurons; (2) DISC1 knockdown in adult-born neurons impairs hippocampal-dependent learning and memory; (3) DISC1 knockdown in adult-born neurons results in other schizophrenia-related phenotypes; (4) Rapamycin rescues the deficits in the water maze and forced swimming caused by DISC1 knockdown in adult-born neurons.Conclusion Although schizophrenia is a neurodevelopmental disorder, our findings suggest that a component of the behavioral and cognitive phenotypes associated with this and perhaps other neurodevelopmental disorders may actually be caused by adult disruptions in DG newborn neurons.Consequently, treatments directed at correcting these molecular and cellular deficits in adult-born DG neurons may have a significant impact on neurodevelopmental disorders such as schizophrenia.
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