Immunohistochemical and electrophysiological characterization of the mouse model for Retinitis Pigmentosa, rd10

In the human disease retinitis pigmentosa (RP) the photoreceptors degenerate over time but the retinal network, in particular the retinal output neurons, the ganglion cells (RGCs) persist, providing a target for electrical stimulation by retinal prostheses. However, remodelling of the retinal network might interfere with this therapeutic approach. In the widely used mouse model of retinal degeneration, rd1, the loss of photoreceptors leads to rhythmic electrical activity of 10 to 16 Hz in the remaining retinal network. This kind of activity is not observed in wild type retina. Recent studies suggest that these oscillations are formed within the electrically coupled network of AII amacrine cells and ON-bipolar cells. Another mouse model, rd10, displays a delayed onset and slower progression of degeneration, making this mouse strain a better model for human RP. In this thesis, the rd10 retina was characterized immunohistochemically and electrophysiologically. It was observed that photoreceptors degenerate over time. Inner retinal cells did not degenerate, but horizontal cells and bipolar cells displayed loss of dendrites. Some somata were slightly misplaced. In horizontal cells sprouting of ectopic processes was also observed. Electrophysiological recordings in vitro using multi electrode arrays (MEA) revealed rhythmic electrical activity in rd10 retina. Regular patterns of local field potentials (LFP) occurred with frequencies between 3 and 5 Hz. Oscillations in LFPs were often accompanied by rhythmic bursts of RGC spikes phase-locked to LFPs. The difference in the oscillation frequency between rd1 and rd10 raised the question whether oscillations have different origins in the two models. A pharmacological analysis suggests that both excitatory as well as inhibitory mechanisms are involved in the generation of spontaneous rhythmic activity in rd10 retina. Oscillations were abolished by blockers of ionotropic glutamate receptors and gap junction blockers. Frequency and amplitude of oscillations were modulated strongly by blockers of inhibitory receptors and to a lesser extent by blockers of HCN channels. In summary, although there are certain differences in the pharmacological modulation of rhythmic activity between rd1 and rd10 the overall pattern looks similar. This suggests that rhythmic activity may be generated by similar mechanisms in rd1 and rd10 retina. Future work must focus on the question, whether this rhythmic activity compromises the efficacy of electrical stimulation by retinal prostheses.