Insights into myelin dysfunction in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.

The Absolute Number of Oligodendrocytes in the Adult Mouse Brain.

The central nervous system is a highly complex network composed of various cell types, each one with different subpopulations. Each cell type has distinct roles for the functional operation of circuits, and ultimately, for brain physiology in general. Since the absolute number of each cell type is considered a proxy of its functional complexity, one approach to better understand how the brain works is to unravel its absolute cellularity and the quantitative relations between cell populations; in other words, how one population of cells is quantitatively structured, in relation to another. Oligodendrocytes are one of these cell types - mainly, they provide electric insulation to axons, optimizing action potential conduction. Their function has recently been revisited and their role extended, one example being their capability of providing trophic support to long axons. To determine the absolute cellularity of oligodendroglia, we have developed a protocol of oligodendrocyte quantification using the isotropic fractionator with a pan-marker for this cell type. We report a detailed assessment of specificity and universality of the oligodendrocyte transcription factor 2 (Olig2), through systematic confocal analyses of the C57BL/6 mouse brain. In addition, we have determined the absolute number (17.4 million) and proportion (about 20%) of this cell type in the brain (and in different brain regions), and tested if this population, at the intraspecific level, scales with the number of neurons in an allometric-based approach. Considering these numbers, oligodendrocytes proved to be the most numerous of glial cells in the mouse brain.

Semi-quantitative analysis of the effects of cyclosporine on remyelination following gliotoxic injection in the brainstem / Análise semiquantitativa dos efeitos da ciclosporina na remielinização após injeção gliotóxica no tronco encefálico

The use of cyclosporine (CsA) has shown to induce an increase in the density of oligodendrocytes near remyelinating areas following the injection of ethidium bromide (EB), a demyelinating agent, in the rat brainstem. This study was designed in order to evaluate if CsA has the capacity of increasing remyelination. In this context, a comparison between the final balance of myelin repair in CsA treated and non-treated rats was assessed using a semi-quantitative method developed for documenting the extent and nature of remyelination in gliotoxic lesions. Wistar rats were submitted to intracisternal injection of 10 microliters of 0.1 percent EB. Some were treated during 31 days with CsA (group III - 10 mg/kg/day by 7 days and, thereafter, 3 times a week, with a minimal interval of 48 hours) by intraperitonial route. Others were not treated with CsA (group I). A control group was planned receiving into the cisterna pontis 10 microliters of 0.9 percent saline solution and following after that the same CsA administration protocol (group II). Results clearly demonstrate that in vivo administration of CsA after EB-demyelinating lesions stimulated oligodendrocyte remyelination (mean remyelination scores of 3.72±0.25 for oligodendrocytes and 1.04±0.39 for Schwann cells) compared to non-treated animals (3.13±0.71 and 1.31±0.62, respectively), although the mechanisms by which this positive CsA effect occurs are unclear.

O uso de ciclosporina (CsA) mostrou induzir um aumento na densidade de oligodendrócitos próximos a áreas de remielinização após injeção de brometo de etídio (EB), um agente desmielinizante, no tronco encefálico de ratos. Este estudo foi desenvolvido a fim de avaliar se a CsA possui a capacidade de acelerar a remielinização. Neste contexto, foi feita uma comparação entre o balanço final de reparo mielínico em ratos tratados ou não com CsA usando-se um método semiquantitativo desenvolvido para documentação da extensão e natureza da remielinização em lesões gliotóxicas. Ratos Wistar foram submetidos à injeção intracisternal de EB a 0,1 por cento. Alguns foram tratados durante 31 dias com CsA (grupo III - 10 mg/kg/dia por 7 dias e, após, 3 vezes por semana, com um intervalo mínimo de 48 horas entre as aplicações) por via intraperitoneal. Outros não foram tratados com CsA (grupo I). Um grupo controle foi desenvolvido recebendo, na cisterna pontina, 10 microlitros de solução salina e seguindo após o mesmo protocolo de administração de CsA (grupo II). Os resultados mostram claramente que a administração in vivo de CsA após lesões desmielinizantes induzidas pelo EB estimulou a remielinização por oligodendrócitos (escores médios de remielinização de 3,72±0,25 para oligodendrócitos e 1,04±0,39 para células de Schwann) em comparação aos animais não-tratados (3,13±0,71 e 1,31±0,62, respectivamente), embora os mecanismos pelos quais este efeito positivo da CsA ocorre sejam desconhecidos.

Ultrastructural study of the effects of cyclosporine in the brainstem of Wistar rats submitted to the ethidium bromide demyelinating model / Estudo ultra-estrutural dos efeitos da ciclosporina no tronco encefálico de ratos Wistar submetidos ao modelo desmielinizante do brometo de etídio

The ethidium bromide-demyelinating model (EB) was used to study remyelination in the brainstem under the use of cyclosporine (CsA). Wistar rats were submitted to intracisternal injection of 0.1 percent EB or 0.9 percent saline solution, and others were taken as histologic controls (group I). Within those injected with EB, some have not received immunosuppressive treatment (II); some were treated by intraperitonial route with CsA (III.E - 10 mg/kg/day). Rats from group III.C were injected with saline solution and treated with CsA. The animals were perfused from 15 to 31 days post-injection collecting brainstem sections for light and transmission electron microscopy studies. After EB injection it was noted the presence of macrophages and non-degraded myelin debris, demyelinated axons, oligodendrocyte or Schwann cell remyelinated axons, groups of infiltrating pial cells, hypertrophic astrocytes and few lymphocytes. Tissue repair of EB-induced lesions in group III.E was similar to that of group II, but with the presence of a higher density of oligodendrocytes near remyelinating areas.

Empregou-se o modelo desmielinizante do brometo de etídio (BE) com o objetivo de estudar a remielinização no tronco encefálico frente ao uso de ciclosporina (CsA). Foram utilizados ratos Wistar, submetidos à injeção de BE a 0,1 por cento ou de solução salina na cisterna pontina, assim como controles histológicos (grupo I). Dos animais injetados com BE, alguns não receberam tratamento imunossupressor (II); outros foram tratados por via intraperitoneal com CsA (III.E - 10 mg/kg/dia). O grupo III.C incluiu animais injetados com salina e tratados com CsA. Os animais foram perfundidos dos 15 aos 31 dias pós-injeção, com colheita de material do tronco encefálico para estudos de microscopia de luz e eletrônica de transmissão. Após injeção de BE, foram observados macrófagos e restos de mielina não-degradada, axônios desmielinizados ou remielinizados por oligodendrócitos e por células de Schwann, grupos de células piais infiltrantes, astrócitos hipertróficos e poucos linfócitos. O processo de reparo das lesões no grupo III.E apresentou-se similar ao do grupo II, porém com maior densidade de oligodendrócitos próximos às áreas de remielinização.