Modules:Retinal Degeneration

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Retinal Degeneration        Best Disease       

Photoreceptor degeneration in humans results from retinal diseases such as retinitis pigmentosa and age-related macular degeneration. Photoreceptor cell death is accompanied by changes in the neural retina Template:Cite pmid;Template:Cite pmid;Template:Cite pmid;Template:Cite pmid;Template:Cite pmid). The local functional implications are not well understood but could compromise spatial processing and transform the retina into a self-signaling neural assembly(Marc and Jones, 2003), making it difficult to use microelectronic retinal prostheses as a rescue strategy. Genetic rescue techniques have there challenges but have windows of opportunity during the degenerative process (Marc and Jones, 2003).

Robert Marc's Stages of Degeneration

  1. Phase I – Rod degeneration; rod photoreceptor outer segments shorten, moving rods through stressed and apoptotic stages. Cone outer segments are truncated as well. Rod neurites sprout and enter the inner retina, extending to the ganglion cell layer.

  2. Phase II – Cone degeneration; rhodopsin levels rise in rods and rods die at a faster rate. Cone gene expression levels change. The subretinal space collapses with fibrosis by Muller cells (glial seal). Every bipolar and horizontal cell appears to be remodeled. Though some bipolar cells die at this stage, quantitatively, it’s a relatively small fraction of the whole.

  3. Early Phase III – Progressive neurite remodeling; Complete loss of sensory retina and glial seal becomes more compacted. This seal becomes bound to the neural retina and cannot be removed. Neurons of the INL begin to remodel. Global cell death becomes statistically significant.

  4. Middle Phase III - Global remodeling; microneuromas (small tumors of abnormal growth) begin to form that include synaptic input from all types of cells. Concurrent and nonbiased neuronal death, cell migration, and rewiring. Rate of death is variable and may depend on the rate of cone cell death. Migration includes bipolar and amacrine cells moving into ganglion cell layer. Movement of amacrine and ganglion cells to the glial seal. Bundles of mixed neurites of all cell types course through the retina. All neurons contain their basic molecular signatures at this point.

  5. Late Phase III – Plateau remodeling; Cell death persists, including substantial cell death in the INL and ganglion cell layer. IPL becomes thinner. Optic fiber thins. RPE alterations are evident.


Retinal Degeneration in Humans

There are 161 known gene defects that result in photoreceptor degeneration (Punzo and Cepko, 2007). Rods are primary targets of these mutations (e.g., RP) and different mutations in a single gene can lead to very different progressions of degeneration (Sung et al., 1994). Retinal degeneration can be cone initiated as well (e.g., ARMD). Cone (COD), Cone-Rod Dystrophy (CORD), and Leber’s Congenital Amaurosis (LCA) can all be initiated by defects in the same genes (Wells et al., 1993). RPE gene defects are also known to lead to photoreceptor degeneration (Marc and Jones, 2003).

Animal Models of Retinal Degeneration

> 90% of the human retina is identical to all experimental mammalian retinae in terms of cone density, structure, and molecular signatures of each cell type (Marc and Jones, 2003).

Model Occurance Gene Cellular Phenotype Human Phenotype
Mouse rd1 Natural PDE6Brd1 Rod cGMP elevation arRP
Mouse rd2 Natural Prph2rd2 Outer segment malformation RP, AMD
Mouse sh-1 Natural Myo7a Usher Syndrome Type B arRP
Mouse orJ Natural Chx10 Retinal Hypcellularity Microthalmia
Rat RCS Natural Mertk Subretinal space debris stress arRP
Chicken rd Natural Gucy1 Rod/Cone cGMP depression rLCA type I
Briard Dog Natural RPE65 Retinoid metabolism failure LCA type II
  • This list is far from comprehensive. For example, there is a rd10 mouse and an rcd1 dog.

Retinal Degneration Over Space and Time

Rod diseases begin in the periphery whereas cone-initiated diseases begin in the macula. However, it should be noted that rodent models do not have true foveae and the distribution of rods and cones is even throughout the retina (Euler and Wassle, 1995; Jeon et al., 1998), thus, diseases such as RP will appear pan-retinally in the rodent. However, the circuitry of rodent retina is nearly identical to peripheral primate retina (Euler and Wassle, 1995), suggesting that using a rodent model of retinal degeneration is relevant to the human condition. Degeneration of the neural retina can be very focal, where areas 100-300 μm in diameter die off, surrounded by areas of healthy neural retina (Marc and Cameron, 2001; Jones et al., 2003).

Many retinal degenerative diseases take years to present. Stargardt’s Disease can take years to present and RP can take decades. Disease progression is generally quite heterogeneous (Marc and Cameron, 2001). In fact, it is not uncommon to see “little islands of surviving cones among rivers of degeneration” (Marc and Cameron, 2001). This effect is also seen in rd mouse models (Ogilvie et al., 1997).

Cell Specific Changes During Degeneration

There are no amacrine or ganglion cell changes during the early stages of degeneration (Peng et al., 2000; Strettoi et al., 2002; Strettoi et al., 2003).

Biolar Cells

  • Physiological: Loss of ON bipolar cells ability to respond to glutamate (Varela et al., 2003). GABAA receptor mediated signaling appears to be enhanced (Varela et al., 2003). With the lack of synaptic input to bipolar cells, one would expect a change in membrane potentials (Marc and Jones, 2003) . Using a technique that tracks iGluR or mGluR6 activation/signaling, Marc found that bipolar cells were silent (Marc et al., 2007).
  • Structural: Early: Loss of dendritic arbors in rod bipolar cells in rd1 mouse (Strettoi and Pignatelli, 2000; Strettoi et al., 2002; Strettoi et al., 2003), however, it should be noted that in the rd1 mouse rods are dying while the dendritic arbors of bipolar cells are forming (Strettoi et al., 2002). Bipolar cells still lose dendritic arbors, even in models that consist of longer living photoreceptors (Furukawa et al., 1999). In both the rd1 mouse (Peng et al., 2000) and the P347L pig (model of RP) (Li et al., 1998) there is evidence of rod bipolar cells sending neurites up into the synapses of cones. Cone bipolar cells lose their dendritic arbors as well, just at a slower rate (Chang et al., 2002). Approximately 30% of rod bipolar cells in the central retina die by pnd 60-90 (early phase III) in the rd1 mouse (Strettoi and Pignatelli, 2000). Late: Death of INL cells comes from displaced RPE cells (Li et al., 1995). The INL is severely thinned (Marc and Jones, 2003). Santos has found that the INL of the macula only suffers an approximately 20% decrease in cell count (Santos et al., 1997). Similarly, Strettoi found approximately a 20% decrease in rod bipolar cells in rd10 mice, with a maximum of 23% loss outwards of 9 months (Gargini et al., 2007). Microneuromas may result in direct bipolar-bipolar synapses and other unusual recurrent circuits, which could create functionally corrupting circuits (Marc and Jones, 2003). There is evidence that CNS cells form compensatory connections to potentially maintain Ca2+ levels in response to decreased synaptic glutamatergic input (Fiala et al., 2002). Glycinergic amacrine cells maintain their normal connections to ON bipolar cells in the degenerating retina (Marc and Jones, 2003). Humayun found that, in the periphery, 40% of the INL is still present in both moderate and severe RP patients (Humayun et al., 1999). Bipolar cell preservation may occur when preceded by clusters of cones (Marc et al., 2007). However, bipolar cells that are greater than ~50 μm outside of this region do not survive. In age-related macular degeneration (ARMD), histology shows that rod bipolar dendritic trees actually into the OPL, rather than retract (Sullivan et al., 2007).
  • Molecular: mGluR6 immunoreactivity is significantly diminished, even in early phase remodeling but there is some evidence of redirection of this protein to the axon (Strettoi and Pignatelli, 2000; Strettoi et al., 2002; Strettoi et al., 2003). mGluR6 may be still expressed at low levels (Dhingra et al., 2000; Dhingra et al., 2002) . Expression of Goα appears to be lost from the OPL, but there doesn’t seem to be any replacement in other parts of the cell (Strettoi et al., 2002). However, expression of Goα appears to continue throughout the bipolar cell (sans the dendritic tree, of course) through all stages of the disease process (Strettoi et al., 2002). Using a technique that tracks iGluR or mGluR6 activation/signaling, Marc found that bipolar cells were silent (Marc et al., 2007). The same Goα mGluR6 expression behavior changes appear to occur in the rd10 mouse (Gargini et al., 2007).

Amacrine Cells

  • Physiological: Even without bipolar cell input, amacrine and ganglion cells revealed iGluR-mediated responses, meaning they are receiving glutamatergic input (Marc et al., 2007).
  • Structural: Some display hypertrophy and are displaced in the human RP retina (Marc and Jones, 2003). Death of INL cells comes from displaced RPE cells (Li et al., 1995). The INL is severely thinned (Marc and Jones, 2003). GABAergic amacrine cells can migrate into the ganglion cell layer (Marc and Jones, 2003). There appear to be no structural changes to starburst, cholinergic amacrines, dopaminergic amacrines, and AII amacrines (Strettoi et al., 2002). Neither their numbers nor stratification appears to change as well (Strettoi et al., 2002).
  • Molecular: No info found but didn’t search too hard. Not critical.

Ganglion Cells

  • Physiological: Even without bipolar cell input, amacrine and ganglion cells revealed iGluR-mediated responses, meaning they are receiving glutamatergic input (Marc et al., 2007). In the baseline activity of rd1 ganglion cells, there is a ~12-19 Hz oscillatory spike activity that is absent in the wild type (Margolis, 2007 – as yet unpublished). Use of synaptic blockers abolishes this behavior. Using current injection methods, Margolis shows that ON, OFF transient, and OFF sustained ganglion cells show similar threshold and suprathreshold behavior to their wild type counterparts (Margolis, 2007 – unpublished). I believe this was without synaptic blockers.
  • Structural: Displaced RPE cells leads to ganglion cell death (Li et al., 1995). IN severe human RP cases, up to 70% of all ganglion cells can die off (Santos et al., 1997). However, Stone concluded that 50-75% of all ganglion cells remained, even in advanced RP (Stone et al., 1992). Humayun found that, in the extramacular regions, 30% of all ganglion cells in moderate RP patients and 20% of all ganglion cells in severe RP patients are still present (Humayun et al., 1999). No ONL was preserved in either group. Morphology of ganglion cells in rd1 mice remained similar to wild type, and similar dendritic size and branching pattern (Margolis, 2007 – not yet published).
  • Molecular: ON ganglion cells express genes coded for HVA Ca channels, whereas OFF ganglion cells express for LVA Ca channels (Margolis, in prep). Need to research this a bit more. And of course, my list of found genes with high expression in ganglion cells.


de:Progressive Retinaatrophie