Inhibitory Effect of LPS on the Proliferation of Oligodendrocyte Precursor Cells through the Notch Signaling Pathway inIntrauterine Infection-induced Rats

Periventricular white matter injury (PWMI)is very common in survivors of premature birth,and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination.How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field.This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms.Lipopolysaccharide (LPS)(300μg/kg)was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury.Corpus callosum tissues were collected at postnatal day 14(P14)to quantify the number of oligodendrocytes,the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP).Furthermore,the expression of Writ and Notch signaling-related proteins was analyzed.The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced,and the expression levels of myelinating proteins were down-regulated.Further analysis showed that the Notch signaling pathway was down-regulated in the LPS-treated group.These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Writ signaling pathway,leading to hypomyelination of white matter.

Nitric oxide production is associated to increased lipoperoxidation and active caspase-3 in demyelinated brain regions of the taiep rat

We previously showed that the increase in nitric oxide (NO) levels and NO synthase (NOS) expression correlate with the progression of reactive astrocytosis and demyelination in the brains of 6-month-old taiep rats. Increased levels of NO can result in high concentration of peroxynitrite and thus cause tissue damage, which consists of lipoperoxidation of the cytoplasmic membrane, such as the myelin, and of apoptotic and necrotic cell-death. On this basis, we studied whether the increased NO production is associated with lipoperoxidation and cell death in the cerebellum and brainstem over the age (1, 3, 6, and 8 months) of taiep rats. The results were compared with those obtained in matched Sprague-Dawley (SD) rats. We measured the levels of nitrites (NO production), malonyldialdehyde, and 4-hydroxyalkenal (lipoperoxidation) in brain tissue homogenates. The three NOS isoforms and cleaved caspase-3 were evaluated by using ELISA and immunostaining techniques. Our results showed that NO production and lipoperoxidation increased in the cerebellum and brainstem as the age of the taiep rats increased compared to SD rats. The overexpression of nNOS and iNOS were in the Purkinje cells, magnocellular neurons, and in oligodendrocytes, whereas the glial cells showed strong cleaved-caspase-3 immunoreactivity. In summary our results suggest that NO plays a role in the demyelination and cell death in the taiep rat.

Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content

Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell lymphoma-associated antigen 5C(cTAGE5C)plays an important role in vesicle trafficking from the endoplasmic reticulum(ER)to Golgi,and conditional knockout(cKO)of Mea6 in the brain significantly affects neural development and brain function.However,whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear.In this study,by using different models of diffusion magnetic resonance imaging,we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter,as well as a significant decrease of cholesterol and triglycerides in brains.Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome,especially the proportion of very long chain fatty acids(VLCFAs).In particular,the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice.The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids(ELOVLs).Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath,myelin lipids,and the pathogenesis of white matter diseases.

Myelin Deficits Caused by Olig2 Deficiency Lead to Cognitive Dysfunction and Increase Vulnerability to Social Withdrawal in Adult Mice

Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together,these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.