Schizophrenia is characterized by disturbances of perception, emotion, social functioning and cognition. Studies suggest that genetics, early environment, neurobiology, psychological and social processes are important contributing factors. Increasing evidence supports an important role of Oligodendrocyte (OL) in the pathogenesis of schizophrenia. Genome-wide gene expression analyses clearly have shown dysregulation of myelination-related genes. Neuropathological and neuroimaging studies demonstrated loss of oligodendrocytes and myelin abnormalities in the brains of schizophrenic patients. Furthermore, patients with various demyelination disorders have psychotic symptoms, indicating a correlation between demyelination and schizophrenia. The OL dysfunction hypothesis, however, has never been experimentally tested due to the lack of suitable animal models. We have revisited the cuprizone (CUP)-induced demyelination model, and found that a low dose (0.2%) of CUP caused OL dysfunction and demyelination primarily in the prefrontal cortex and the corpus callosum in C57BL/6J mice. Our data has found that the OL dysfunction, degeneration, and demyelination in this model were accompanied by the development of schizophrenia-like behaviors, and that enhancing remyelination by promoting OL proliferation and maturation significantly improved these behavioral changes.