摘要Objective Schizophrenia is a complex neuropsychiatric disorder characterized by cognitive,affective,and behavioral abnor-malities.Existing treatments have yielded limited effects on improving cognitive function.Recent studies have identified the abnormal differentiation of hippocampal neural stem cells(NSCs),neuronal loss,and dysregulated proliferation of astrocytes as significant pathological mechanisms contributing to the symptoms of schizophrenia.Impaired hippocampal neurogenesis may lead to emotional and cognitive deficits and biases in learning and memory,indicating that NSC differ-entiation is critical.NEP1-40,a Nogo-A receptor inhibitor,has shown promise for nerve protection and repair promotion.However,the effects of NEP 1-40 on stem cell differentiation,the reduction in neuronal apoptosis,and the amelioration of schizophrenia-like behaviors have not been adequately investigated.This study examined the influence of NEP1-40 on NSC differentiation,hippocampal neuronal apoptosis,and proliferation in adolescent mice,along with its potential to enhance cognitive and behavioral outcomes in MK-801-induced schizophrenia mouse models.Methods In in vivo experiments,a schizophrenia mouse model was successfully established.Subsequently,behavioral tests were conducted,followed by Western blotting(WB)and immunofluorescence(IF)analyses.In in vitro settings,NSCs were cultured and transfected.Flow cytometry,along with WB and IF assays,was employed to evaluate the effects of NEP1-40.Results Schizophrenia-like behaviors in mice were significantly improved with the overexpression of NEP 1-40.Compared with the model group,the NEP 1-40 treatment group presented increased expression of a neuronal marker(Tuj1),reduced expression of an astroglial marker(GFAP),and decreased hippocampal neuronal apoptosis.NSC differentiation was assessed by quantifying the number of BrdU-positive cells coexpressing Tuj1 and GFAP in the hippocampal dentate gyrus.NEP 1-40 treatment led to an increase in BrdU/Tuj1-positive cells and a reduction in BrdU/GFAP-positive cells.In cellular studies,NEP1-40 overexpression similarly increased the number of Tuj1-positive cells,reduced the number of GFAP-positive cells,decreased the degree of neuronal apoptosis,and promoted neuronal proliferation.Conclusion These findings demonstrated the neurogenic effects of NEP1-40 on NSCs and their potential to mitigate schiz-ophrenia-like behaviors in vivo.