A Study On The Correlation Between Myelin Abnormalities In The Central Nervous System And Psychiatric Disorders

Schizophrenia is a severe psychiatric disorder with an annual incidence rate ofapproximate0.4-1%worldwide. It is a kind of disease which affects the young adults mostoften. There is no satisfactory therapy for schizophrenia as yet, which will inevitablyimpose a great burden on schizophrenic patients, the society and the countries,physiologically, psychologically and economically. The pathogenesis of schizophreniaremains unknown. It is generally accepted for the present that schizophrenia is a diseaseattributable to many factors including genes, environment, development, etc. Recent studieshave shown that schizophrenia is closely associated with myelin abnormalities. A DNAmicroarray study has examined the gene expression levels in the brain of patients withschizophrenia and the results demonstrated that a group of myelin-related genes (MAG,Transferrin, MAL, CNP, Gelsolin and ErbB3) were significantly downregulated. Imagingstudies by magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) reveallateral ventriculomegaly, atrophic temporal lobe and superior temporal gyrus, white matterdeficit, and abnormalities in basal ganglia, corpus callosum, thalamus, cerebellum and othersubcortex structures in the brain of patients with schizophrenia. Postmortem examination ofschizophrenic patients confirms myelin maldevelopment and oligodendrocyte (OL)dysfunction in their central nervous system. These findings imply a causal relationshipbetween myelin abnormalities and onset of schizophrenia. Provided that myelinabnormalities are among the primary contributing factors for schizophrenia, it is reasonableto speculate that factors sensitive to myelin injury, which can account for myelinmaldevelopment or demyelination, may well induce schizophrenia-like behavioral changes.Age is an important factor that has to be considered in schizophrenia as well as indemyelination. Epidemiological analysis demonstrates that the usual onset of schizophreniais between15and35years old, with50%of schizophrenic patients first developing thesymptoms in their twenties. Other demyelinating diseases such as multiple sclerosis are alsofrequently seen among young people. Olig2is one of the bHLH transcription factor Olig family members which plays a crucial role in OL development and myelination. Recently,genetic polymorphism analysis has proved that abnormal expression of Olig2is readilyinvolved in schizophrenia among patients from Han ethnic group and European countries.In the present study, we employed a demyelination and a development mice model toevaluate the contributions of age or Olig2to myelin injury susceptibility or myelinmaldevelopment that correlate with schizophrenia-like behaviors. Our results would providemore evidence in support of the aforementioned hypothesis that myelin abnormalities havebeen involved in the pathogenesis of schizophrenia, and thus it is of great significance toprovide new therapeutic strategies for schizophrenia and other releated disorders.The study is composed of two parts:Part1: Correlation between age-related and cuprizone-induced demyelinationand schizophrenia-like behavioral changesWe established a cuprizone-induced acute demyelination model using mice withdifferent ages. Body weight measurement and LFB staining were conducted to determinewhether the model had been successfully established; behavioral tests were then performedto observe whether demyelination would induce schizophrenia-like behaviors; finallyimmunohistostaining and Western blot analysis were applied to observe levels ofdemyelination, mature OL damage and astrocytosis in corpus callosum and cortex of mousebrain. The potential correlation between age and demyelination sensitivity, as well as thecontributions of mature oligodendrocytes and astrocytes in the process of demyelination,have been investigated based on the outcomes.The results were as follows:1. The cuprizone-induced acute demyelination model was successfully established;body weight measurement and LFB staining confirmed body weight loss and demyelinationin model mice.2. In the open field test, the locomotive distances in the whole field were comparablebetween model mice and control mice of the same age (p>0.05); the locomotive distances ofmodel mice in the central area were significantly shorter than that of control mice in eachage group (p<0.05), and this decrease in distance was more significant in the younger agegroup.3. A significant downregulation of MBP was detected in corpus callosum and cortex areas of young adult mice treated with cuprizone when compared with adult and aged mice(p<0.01).4. A decrease in the number of CC1positive OL cells was observed in corpus callosumand cortex areas of model mice treated with cuprizone in each age group, and the decreasewas more significant in young adult mice than in adult and aged mice (p<0.01).5. Proliferation of GFAP positive astrocytes (ASTs) was observed in corpus callosumand cortex areas of CPZ mice, and the level of proliferation was more significant in youngadult mice than in adult and aged mice (p<0.01).Based on the above experimental results, we can reach the following conclusions:young adult mice are more sensitive to demyelination compared with adult and aged mice inthat they show higher proneness to demyelination; behavioral tests demonstrate thatabnormalities of psychiatric behaviors are more evident in young adult mice; the process ofdemyelination is accompanied with age-related damage of mature oligodendrocytes andastrocytosis. Therefore, age-dependent sensitivity of mature oligodendrocytes todemyelination and astrocytosis may be the underlying causes that can account for the aboveconclusions.Part2: Correlation between Olig2knockout myelin development andschizophrenia-like behavioral changesIn this part, the function of transcription factor Olig2in myelin development wasobserved by knocking out Olig2in OLs using CNP promoter; behavioral tests (open fieldand elevated plus-maze tests) were then performed to evaluate behavioral changes in Olig2knockout mice; and finally a cuprizone-induced acute demyelination model was establishedusing the Olig2knockout mice to observe the influence of Olig2on myelin damage.The results were as follows:1. Knockout of Olig2in OLs obstructed myelination in nomal brain development.2. Knockout of Olig2inhibited differentiation of OLs, but showed little influence oncell proliferation.3. Behavioral tests confirmed abnormalities of psychiatric behaviors in Olig2knockoutmice in that they showed stronger desire for exploration and stronger curiosity whencompared with control mice.4. Olig2knockout mice were more sensitive to cuprizone-induced demyelination. Based on the above experimental results, we can reach the following conclusions:knockout of transcription factor Olig2can affect oligodendrocyte differentiation andthereby affect myelin development; Olig2knockout mice tend to conduct abnormalpsychiatric behaviors and exhibit more sensitivity to myelin damage. Taking together, themyelin maldevelopment resulted by abnormalities of transcription factor Olig2may closelyassociated with the onset of schizophrenia and other psychiatric disorders.