Cytoarchitectural Defects Secondary To Experimentally Induced Oligodendrocyte Death In The Adult And Developing Central Nervous System

The ability of the central nervous system (CNS) to execute sophisticated functions with remarkable efficiency relies on extensive cross-talk between a number of specialized cell types. Myelination is a quintessential example of such cellular communication in which highly specialized oligodendroglia extend compacted spirals of cell membrane around individual axons of multiple neurons. Functionally similar to the insulation that encases household electrical wiring, myelin accelerates the conduction of electrical signals that underlies complex behavioral outputs such as movement and sensation. A recent approach to better understand the dynamic relationship between axons and oligodendrocytes has been the development of models in which oligodendrocytes can be experimentally eliminated from living tissues. However, confounding factors inherent in each of the existing models complicate data interpretation. Limitations include dubious cell specificity, a mechanism of cell death that is not physiological, and/or the requirement of a stimulated peripheral immune system, a condition often associated with pathology. The current work proposes a novel experimental model that circumvents these issues. The basic premise of the model is that activation of a genetically encoded cell death program that is inherent in most cells can be experimentally controlled and targeted specifically to myelinating oligodendrocytes. In this way, oligodendrocytes can be eliminated from living tissue by a physiological mechanism that by definition does not stimulate an immune response. By analyzing changes in natural phenomena in the absence of oligodendrocytes, if all else is equal, it is possible to begin to understand their roles in complex cellular processes such as developmental myelination and adult myelin regeneration, both of which are critical for nervous system function. In the current studies, oligodendrocytes were depleted in both the adult and developing central nervous systems. At both ages, myelin was degraded by twenty-four hours after oligodendrocyte apoptosis resulting in the recruitment, activation, and partial phagocytosis by resident microglia. Peripheral T-lymphocytes were notably absent until seven days after induced apoptosis. The ensuing proliferation of oligodendrocyte progenitor cells was selective and local, implying an efficient and space-delineated mechanism for cell replacement even in the adult CNS. Depletion of oligodendrocytes during neonatal development resulted in severe myelin deficiency that recovered almost entirely within two weeks. Pilot studies indicate that heavy demands on the plasticity of a developing CNS render it susceptible to myelin challenges later in life. The iCP9 model of inducible oligodendrocyte apoptosis provides information useful to both basic scientists and clinicians. On a basic level, the iCP9 technology provides a tool for studying brain function with only a fraction of the oligodendrocytes and without involving or perturbing the immune system. Given that myelin destruction is hallmark pathology of multiple sclerosis, the current studies also propose novel ideas and new models to explore the underlying biological basis of an enigmatic disease.