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Investigating Early Retinal Remodeling and Secondary Cone Degeneration in Retinitis Pigmentosa


In retinitis pigmentosa (RP), primary rod degeneration leads to the secondary degeneration of cones, resulting in loss of normal retinal input. Retinal function is further disrupted by downstream retinal remodeling. The mechanisms underlying these degenerative processes are currently incompletely understood. In my thesis research, I use whole-cell electrophysiology recordings from retinal slices to investigate changes in retinal physiology during retinal degeneration.

In the first section of my thesis, I investigate the changes in the rod-to-rod bipolar cell synapse during the early stages of degeneration in the CNGB1 KO mouse model. Previous studies show that rod bipolar cells lack light-evoked responses prior to the loss of light responses in rods, despite intact rod-to-rod bipolar cell synapses. Using a weak mGluR6 antagonist, CPPG, I show that although rod bipolar cells lose light-evoked responses they retain the molecular machinery required to support mGluR6-driven responses. These results indicate that the breakdown in synaptic transmission between rods and rod bipolar cells is most likely due to presynaptic dysfunction with impaired glutamate release from rods.

In the second section of my thesis I characterized changes in cone membrane physiology during secondary cone degeneration by performing whole-cell patch clamp recordings from degenerating cones in rd10 mice. I show that, despite significant morphological changes, including the loss of the outer segment and cone pedicle, cones maintain relatively normal membrane physiology. What’s more, cones continue to produce small light-evoked responses even at late stages of degeneration, and these responses are transmitted on to second-order neurons. These findings are encouraging for future research aimed at reactivating dormant cones to restore vision to patients with RP.

In the final section of my thesis I explore the evolutionary origins of one of the vertebrate retina’s most unique features: the use of the metabotropic glutamate receptor in the ON bipolar cell pathway. My results indicate that the division of light information into ON and OFF pathways at the first synaptic connection and the mediation of the ON pathway through a metabotropic glutamate receptor evolved over 500 million years ago and is a fundamental feature of the vertebrate retina.

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