Inner Retina Signaling and Well-Preserved Vision during Photoreceptor Degeneration in the P23H Retinitis Pigmentosa Model

Abstract

Purpose : The degeneration of rod photoreceptors associated with retinitis pigmentosa (RP) also triggers remodeling in the synaptic and inner nuclear layers of the retina. It is not fully understood how this remodeling affects the light-induced signaling from photoreceptors to ganglion cells, and if it is detrimental to vision. The goal of this study is to determine how photoreceptor signal transmission and overall vision are affected during progressive rod degeneration in the P23H RP model.

Methods : Optical coherence tomography was used to assess the extent of rod degeneration in 1, 3, and 5 mo. old Rho^P23H/Wt (P23H) and age-matched wild-type (WT) mice. Visual acuity was determined using an optomotor response test. The function of the cone pathway was measured by photopic in vivo electroretinography (ERG). Rod photoreceptor and bipolar cell signaling was assessed by ex vivo ERG using dark-adapted isolated retinas perfused with medium containing barium. The bipolar cell component (R_b) of the ex vivo ERG signal was isolated by subtracting light responses recorded after blocking glutamatergic synaptic transmission with DL-AP4. The rod photoreceptor component (R_p) was determined in the presence of DL-AP4 and barium.

Results : Average outer nuclear layer thickness in the central retina was ~45 µm in 1 mo. P23H mice (58 µm in WT mice), and decreased an additional 50% at 3 mo. and further by 25% by 5 mo. of age. Visual acuity was initially normal in P23H mice and only declined by ~10% in 5 mo. mutant mice. Photopic in vivo ERG b-wave responses were sensitized in amplitude but slowed slightly at 1 and 3 mo. of age in P23H mice. The maximal ex vivo ERG response amplitude (rod component) decreased gradually from 240 µV in 1 mo. to 81 µV in 5 mo. P23H mice, while it was ~400 µV in littermate WT mice regardless of age. Surprisingly, the bipolar cell component R_b was similar in control and 1 mo. P23H mice. The R_p-R_b plot changed with age in P23H mice, demonstrating sensitization of bipolar cells to the remaining photoreceptor input.

Conclusions : We show that behaviorally relevant vision is well-preserved despite extensive photoreceptor degeneration and dysfunction in a P23H mouse model of RP. Potentiation of the photoreceptor – bipolar signaling may contribute to this phenomenon and warrants further investigation.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.