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David Calkins; Intrinsic mechanisms of retinal ganglion cell degeneration in glaucoma. Journal of Vision 2009;9(14):14. doi: 10.1167/9.14.14.
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© ARVO (1962-2015); The Authors (2016-present)
The degeneration of the retinal ganglion cell neuron and its axon in glaucoma involves several important contributors extrinsic to the ganglion cell itself. These include immunological, vascular and glial processes. Also involved are biomechanical mechanisms, which stress the ganglion cell axon as it passes unmyelinated and presumably vulnerable through the optic nerve head in forming the nerve. During disease pathogenesis, this complex medley changes with age and ocular pressure, the two most prominent risk factors for glaucoma. Similarly, the survival of the ganglion cell depends not only on these extrinsic influences in its milieu, but also on its intrinsic response to age and pressure. Key indicators of this intrinsic response include active axonal transport to and from the brain, cytoskeletal integrity, genetic reprogramming, synaptic maintenance and cationic activity, particularly that due to Ca2+. Finally, ganglion cell survival in glaucoma ought to depend also on the response of its targets in the brain to glaucomatous stressors like age and ocular pressure. This target response includes changes in the regulation of trophic factors, such as BDNF, as well as other cascades involved in injury-induced plasticity.
Research in our laboratory has focused recently on multiple aspects of the response of the ganglion cell, its axon and target sites in the brain in glaucoma. Using both chronic and acute rodent models, we have found that this response includes several pre-degenerative changes. These include diminished active transport between the retina and brain that evolves prior to loss of the myelinated tract and ganglion cell presynaptic terminals at target sites. Transport declines following a distal (brain) to proximal (retina) progression whose spatial pattern is sectorial, mimicking vision loss in glaucoma. With aging, loss of transport requires less ocular pressure as a pedestal insult to reach a significant magnitude. Declining transport in the colliculus evolves with focal upregulation of BDNF in the deficit region. The loss of transport in the superior colliculus, the primary target for ganglion cell axons in the rodent brain, can be predicted using Mn2+-enhanced magnetic resonance imaging, a surrogate probe for Ca2+-dependent activity. Finally, we have found that the ganglion cell expresses novel cation channels that are implicated in gating Ca2+ with exposure to pressure.
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