| The mammalian retina is comprised of 55--60 cell types mediating transduction of photic information through visual preprocessing channels. These cell types fall into six major cell superclasses including photoreceptors, horizontal, amacrine, Muller and ganglion cells. Through computational molecular phenotyping, using amino acids as discriminands, this dissertation shows that the major cellular superclasses of the murine retina are subdivisible into the following natural classes: 1 retinal pigment epithelium class, 2 photoreceptor, 2 bipolar cell, 1 horizontal cell, 15 amacrine cell, 1 Muller cell, and 7 ganglion cell classes.; Retinal degenerative diseases like retinitis pigmentosa result in loss of photoreceptors, which constitutes deafferentation of the neural retina. This deafferentation, when complete, is followed by retinal remodeling, which is the common fate of all retinal degenerations that trigger photoreceptor loss. The same strategy used to visualize cell classes in wild type murine retina was applied to examples of retinal degenerative disease in human tissues and naturally and genetically engineered models, examining all cell types in 17 human cases of retinitis pigmentosa (RP) and 85 cases of rodent retinal degenerations encompassing 13 different genetic models. Computational molecular phenotyping concurrently visualized glial transformations, neuronal translocations, and the emergence of novel synaptic complexes, achievements not possible with any other method. The fusion of phenotyping and anatomy at the ultrastructure level also enabled the modeling of synaptic connections, illustrating that the degenerating retina produces new synapses with vigor with the possibility that this phenomenon might be exploited to rescue vision. However, this circuitry is likely corruptive of visual processing and reflects, we believe, attempts by neurons to find synaptic excitation, demonstrating that even minor rewiring seriously corrupts signal processing in retinal pathways leaving many current approaches to bionic and biological retinal rescue unsustainable.; The ultimate conclusion is that the sequelae of retinal degenerative disease are far more complex than previously believed, and schemes to rescue vision via bionic implants or stem/engineered cells are based on presumed beliefs in preservation of normal wiring and cell population patterning after photoreceptor death. Those beliefs are incorrect: retinal neurons die, migrate, and create new circuitries. Vision rescue strategies will need to be refined. |
