Abstract
Purpose::
Retinal prosthesis and stem cell therapies to treat retinitis pigmentosa (RP) rely on the notion that second- and third- order retinal circuitry remains intact. However, recent work suggests that the remaining retinal circuitry undergoes significant remodeling in response to the loss of photoreceptor input, making the efficacy of such therapies uncertain. Using the rd10 mouse model of RP that more closely mimics human autosomal recessive RP than the more commonly studied rd1 mouse, we evaluated the progression of remodeling of second- and third-order retinal circuits.
Methods::
Sections of rd10 mouse retina were collected at timepoints representing varying stages of degeneration: P30 (postnatal day 30), P50, PM3.5 (postnatal month 3.5), PM7.5, and PM9.5. Sections were immunolabeled using well-known cell and synapse specific markers to assess cell morphology and synaptic organization. Age-matched c57BL/6 mouse retina was used for controls.
Results::
Changes occurred progressively in the inner retina following photoreceptor loss. Over time, rod bipolar cell dendrites retracted, cell bodies migrated, and axon terminals changed morphology and some mis-stratified in the IPL. Furthermore, mGluR6 receptors were gradually lost from rod bipolar cells and were absent by PM9.5. However, ON-OFF stratification of cone bipolar terminals was largely preserved until at least PM9.5. Horizontal cells initially sprouted ectopic processes into the ONL and INL at P30 - P50, but lost these sprouts and normal processes at later stages. Horizontal cells showed reduced GluR4 labeling at later stages. Putative ectopic conventional synapses formed in the INL by PM9.5. Muller cell gliosis was evident by P30 and became more pronounced as degeneration progressed. Despite these changes, synaptic protein distribution in the IPL was approximately normal and several amacrine cell types retained their normal lamination in the IPL up to PM9.5.
Conclusions::
The rd10 mouse retina undergoes extensive remodeling out to PM9.5. However, the retinal circuitry retains many normal features even when faced with loss of light-driven input from photoreceptors for several months. These data suggest that some inner retinal circuits retain their organization for a protracted length of time, giving hope to early interventions.
Keywords: retinal degenerations: cell biology • retinal connections, networks, circuitry • plasticity