Effect of Sox10 on remyelination of the hippocampus in cuprizone-induced demyelinated mice.

OBJECTIVE: The low number of oligodendrocytes (OLs) in the hippocampus of patients with schizophrenia suggests that hippocampal demyelination is changed in this condition. Sox10 is expressed throughout OL development. The effect of Sox10 on myelin regeneration is unknown. This study aimed to analyze changes in Sox10 expression in the hippocampus and its regulatory role in hippocampal myelin regeneration in a mouse model of demyelination. METHODS: Mice were fed 0.2% cuprizone (CPZ) for six weeks to establish the acute demyelinating model (CPZ mice). Behavioral changes of these mice were assessed via open field and tail suspension tests. The ultrastructure of the myelin sheaths in the hippocampus was observed by transmission electron microscopy. The expression levels of myelin sheath-related proteins and the transcription factor Sox10 were detected via immunohistochemistry and Western blots. Furthermore, Sox10-overexpressing adeno-associated virus was injected into the hippocampus after establishing the demyelinating model to investigate effects of Sox10 on remyelination. RESULTS: CPZ mice showed abnormal behavioral changes, a large number of pathological changes in the myelin sheaths, and significantly reduced protein expression of the myelin sheath markers myelin basic protein and proteolipid protein. This confirmed that the demyelinating model was successfully established. Meanwhile, the protein expression of the oligodendrocyte precursor cell marker neural/glial antigen 2 (NG2) increased, whereas Sox10 expression decreased. After Sox10 overexpression in the hippocampus, the abnormal behavior was improved, the ultrastructure of the myelin sheaths was restored, and the expression of myelin sheath protein was reversed. NG2 expression was upregulated. CONCLUSION: Overexpression of Sox10 promotes hippocampal remyelination after CPZ-induced acute demyelination.

NEP1-40 alleviates behavioral phenotypes and promote oligodendrocyte progenitor cell differentiation in the hippocampus of cuprizone-induced demyelination mouse model.

BACKGROUND: Studies have demonstrated that the failure of oligodendrocyte precursor cells (OPCs) differentiation as a major cause of remyelination failure in demyelinating disease. The reasons for this failure are not completely understood. We hypothesized that the present of myelin debris in CNS play an important role in poor OPCs differentiation in the mouse model of demyelinating disease. METHODS: Mice were fed by the food mixed with normal or 0.2 % cuprizone (CPZ) for 6 weeks. Then the learning and memory impairment were tested by Morris water maze test. The spontaneous alternation behavior and depression-like symptoms were assessed by tail suspension test and open filed test. The number of OPCs and oligodendrocytes were counted by immunofluorescence. After exposed to CPZ for 6 weeks, the mice were then receiving stereotactic injection of NEP1-40 into the CA3 of hippocampus. The behavioral, learning and memory changes were assessed by tail suspension test and open field test. The differentiation of OPCs were detected by immunofluorescence and western blot. RESULTS: The mice in CPZ group are more likely to show signs of depression and they showed impairment of long-term learning and memory function. The differentiation of OPCs were impaired in CPZ group. We found that mice treated with NEP1-40 showed less depression-like symptom in TST and higher locomotor activity in the OFT than the mice treated with PBS. CONCLUSIONS: Our study suggest that NEP1-40 can promote OPC differentiation and survival. Further study should focus on the effect of NEP1-40 on the differentiation and survival of OPCs in vitro.