Oligodendroglial Signaling In The Regulation Of Myelin Development And Brain Function During Adolescence

Schizophrenia is a serious mental illness.It usually onsets in late adolescence or early adulthood and affects life afterwards.White matter abnormality is one of the pathological features of schizophrenia,but the pathological mechanism of white matter abnormality and its relationship with schizophrenia are not clear.ErbB receptors and their ligands are susceptibility genes of schizophrenia.It has been demonstrated that NRG1-ErbB signaling is essential for the myelination of Schwann cells in the peripheral nervous system.However,whether it plays important roles for central myelin development is still controversial.Adolescence,when schizophrenic patients have highly incidence to have the first episode,is the age for rapid development of white matter.Therefore,studying the effects of ErbB signaling pathway on white matter development may be an important way to understand the pathogenesis of schizophrenia.We have specifically manipulated the ErbB activity in the stage of oligodendrocyte progenitor cells(OPCs)to newly formed oligodendrocytes(NFOs),as well as that of mature oligodendrocytes(MOs)in adolescent mice.We have found in our previous work that aberrant activation or inhibition of ErbB receptors in the oligodendrocyte lineage can lead to pathogenesis or hypomyelination in mice.In the present study,we further explored the molecular and cellular mechanisms that ErbB signaling regulates oligodendrocyte development in adolescence and its impact on brain function.First,we characterized the targeting specificities to adolescent oligodendrocyte stages of mouse tools used in this study,and tested the signal intensities of all ErbB receptors in the white matter of inducible mutant mice generated by these mouse tools.It is validated that we have specifically activated or inhibited the ErbB signaling pathway in oligodendrocytes at different stages in adolescence,and the functionally activated ErbB receptors are revealed in the different oligodendrocyte stages.By analyses with RNA-seq,in situ hybridization,and immunofluorescence staining,we found that although ErbB inhibition in oligodendrocytes has not affected myelin development in adolescent mice,ErbB activation in OPC-NFOs during adolescence causes a prolonged transition to MO stage for NFOs,while ErbB inhibition in OPC-NFOs shortens the transition to MO stage for NFOs and reduces the myelination ability of NFOs.In behavioral tests,both demyelination and hypomyelination caused by ErbB activation in oligodendrocytes affects motor function severely in mice,While hypomyelination caused by ErbB inhibition in OPC-NFOs affects motor coordination.Although ErbB inhibition in OPC-NFOs or MOs has different effects on the myelin of adult mice,they both lead to working memory deficits.These results show that oligodendrocytes at different cellular stages in adolescence are sophisticatedly regulated by ErbB signaling.Disrupted ErbB signaling can cause brain dysfunction by affecting the development or integrity of myelin,or leads to cognitive deficits by affecting the myelin-independent function of oligodendrocytes.