2008 Annotation: RP is a progressive disease (similar to temporal lobe epilepsy), rather than a focal event that scissors off photoreceptors. Framing the discussion in that manner properly brings understanding of the molecular and structural mechanisms of negative CNS neuroplasticity to bear on the problem of vision restoration.

• Implant technologies presume substantial survival of retinal outflow channel architectures.
  The retina is complex and forms approximately 14 patterned outflow channels, realized as ganglion cells. The mammalian retinal parts list includes 1 rod class, 1 rod horizontal cell, 1 rod bipolar cell, 2-3 cone classes, 1-3 cone horizontal cells, 9+ cone bipolar cells, 27 amacrine cells, and about 15-20 ganglion cells. Thus, about 60-70 cellular devices form the outflow channels. Our next challenge will be to trace the wirings that create outflow channels; resolve synaptic transduction assemblies in terms of molecular signaling and electromorphology; reconcile wiring models with physiological data; and produce a complete, validated model of retinal vision. Semiconductor technologies can produce devices that mimic retinal outflow subsets in silico, though none reproduce cone vision. We will assume that barrier transcended. In theory, subretinal implants drive remnant circuits with cone-like inputs and epiretinal implants drive ganglion cell channels by mimicking bipolar-amacrine cell networks. Both schemes require survival of retinal neurons to drive perceptual and oculomotor systems, and presume no alterations in cell patterning or connectivity, nor any corruptive signal invasion into retinal networks. Subretinal strategies uniquely require positioning within the subretinal space. These presumptions (preservation of topology, cell numbers and wiring) are false for most retinal degenerations.
  
  
• Photoreceptor degenerations trigger negative remodeling of retinal outflow channel architectures.The retina is a bilaminar device. The sensory retina is composed of photoreceptors and is the photon transducer layer. The neural retina, composed of the remaining neuron classes is the image processor layer. It has long been claimed that the neural retina remains unchanged after the death of the sensory retina. This is incorrect. The neural retina enters a protracted tertiary phase of remodeling characterized by (1) disruption of topology by glial hypertrophy and neuronal migration, (2) neuronal cell death; and (3) extensive rewiring.

  2008 annotation: It is still common to find assertions that the neural retina is essentially normal after photoreceptor death. That is patently incorrect.

  • Neural retinal topology is corrupted in retinal degenerations. After loss of the cones, all Muller cells enter a hypertrophic response phase where the perikarya migrate throughout the retina and their processes hypertrophy to form distal and proximal seals, as well and columns or walls of glia that transect the neural retina. The distal glial seal obliterates the subretinal space and there is no place to insert a subretinal implant. The seals are imperfect and their irregular AC admittance properties will likely corrupt implant current patterns. All glial surfaces appear to be guides for unregulated neuronal migration. Many amacrine cells migrate to both the distal and proximal retinal borders, while bipolar cells can become misplaced to the ganglion cell layer and occasional ganglion cells move into the remnant inner nuclear layer.

    2004 annotation: These concerns remain unaltered. Indeed, circumstances are likely even more complex in AMD, as we now know that Muller glia can perforate Bruch's membrane, invade the choroid, and trigger concurrent exodus of neurons from the retina.

  • Neuronal cell death is extensive in retinal degenerations. Though many neurons persist after death of the sensory retina, all are susceptible to cell death in varying fractions and patterns. Focal depletion of the inner nuclear layer is common and some genetic types of photoreceptor degenerations express massive ganglion cells loss in large patches of retina.

    2004 annotations: Again, cell death can be even more aggressive in AMD and many prior studies of cell loss used counts of retina that still possessed ONL somas (which inhibits much neuronal cell death) and did not use validated neuronal markers.

  • Aberrant rewiring attends retinal degenerations. The most dramatic changes in remodeling retinas include the elaboration of new neurite fascicles and the formation of new circuitry in microneuromas across the retina, next to the distal glial seal. New circuitry includes aberrant re-entrant bipolar cell circuits and extensive changes in synaptic architecture. Modeling of new circuits shows that all are corruptive and many form resonant circuits. Thus, the remnant neural retina is no longer an effective image processor.
    

    2004 annotations: This doesn't include the clearly corruptive neurite retraction by bipolar cells, signal transduction phenotype decomposition, horizontal cell remodeling and partial cell loss, and changes in ganglion cell signaling that occur early in retinal degenerations. It is unlikely that any retinal cell remains normal following the onset of most retinal degenerations.

    2008 Annotations: Our recent work now shows that remodeling goes beyond rewiring and morphological change and includes molecular reprogramming. Passive anatomy alone will not reveal the scope of neural revisioning in response to retinal diseases such as RP.

• Summary: Put simply, the key presumptions of implant technologies are false for most retinal degenerations. Current implant validation schemes employ model systems that do not mimic true post-degeneration neural retinas. Assertions on web sites, in the media and in peer-reviewed literature that the remnant neural retina remains essentially normal after photoreceptor degeneration are misleading and should cease.

  2004 annotations: Circumstances are not much different today. Although appreciation of these issues is more common, open acknowledgment is rare.