Abstract
The optic nerve represents one of the simplest regions of the CNS and has been useful in developing an understanding of glial development and myelination. While the visual system is frequently affected in demyelinating conditions, utilizing the optic nerve to model demyelination/remyelination studies has been difficult due to its accessibility, relatively small size, and dense nature that makes direct injections challenging. Taking advantage of the lack of oligodendrocytes and myelination in the mouse retina, we have developed a model in which the induction of apoptosis in mature oligodendrocytes allows for the selective, non-invasive generation of demyelinating lesions in optic nerve. Delivery of an inducer of oligodendrocyte apoptosis by intravitreous injection minimizes trauma to the optic nerve and allows for the assessment of oligodendrocyte death in the absence of injury related factors. Here we show that following induction of apoptosis, oligodendrocytes are lost within 3 days. The loss of oligodendrocytes is associated with limited microglial and astrocyte response, is patchy along the nerve, and results in localized myelin loss. Unlike in other regions of the murine CNS, where local demyelination stimulates activation of local oligodendrocyte precursors and remyelination, optic nerve demyelination induced by oligodendrocyte apoptosis fails to recover and results in persistent areas of myelin loss. Over time these chronic lesions change cellular composition and ultimately become devoid of GFAP+ astrocytes and OPCs. Why the optic nerve lesions fail to repair may reflect the lack of early immune responsiveness and provide a novel model of chronic demyelination.
Highlights
Demyelinating diseases such as multiple sclerosis (MS) are characterized by lesions in CNS white matter where myelin and oligodendrocytes have been lost, and in most active lesions there is an infiltration of cells of the peripheral immune system [1, 2]
The degree of dye labeling was similar throughout the nerve and the nerve appeared undamaged indicating that injection in the vitreous provides an effective conduit for drug delivery to the intact optic nerve
Recent studies demonstrated the ability to selectively ablate oligodendrocytes in the CNS of a novel transgenic mouse line in which an inducible form of caspase 9 linked to a DsRed reporter is driven by a fragment of the myelin basic protein promoter [11]
Summary
Demyelinating diseases such as multiple sclerosis (MS) are characterized by lesions in CNS white matter where myelin and oligodendrocytes have been lost, and in most active lesions there is an infiltration of cells of the peripheral immune system [1, 2]. To provide insights into the mechanisms mediating CNS demyelination and to develop potential therapeutic approaches for MS and related diseases, a number of animal models have been established These fall into two distinct categories: those that utilize the induction of immune mediated damage to CNS white matter [4] and those that utilize a gliotoxin to drive local demyelination [5]. For example the most commonly used immune-mediated model of MS is experimental allergic encephalomyelitis (EAE) where injection of specific peptides of myelin proteins such as MBP, PLP or MOG into a susceptible host genotype combined with stimulation of the immune system results in wide spread infiltration of immune cells and myelin loss [4] This model has been useful in identifying therapies that affect the immunological component of MS but less effective in identifying therapies that influence the neuroprotection and remyelination components of MS. Gliotoxin models such as cuprizone toxicity, induced by feeding chow containing copper chelator
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