Maintained scotopic contrast sensitivity is associated with increased rod to rod-bipolar cell signal transmission in retinitis pigmentosa

Abstract

Purpose : Patients with retinitis pigmentosa (RP) can retain vision well into adulthood but the mechanism for this remains unknown. We hypothesize that compensatory changes in the rod-rod bipolar cell (RBC) synapse promote transmission of light signals and vision during rod degeneration. We test this using an established Rho^P23H/WT knock-in mouse model of RP (P23H).

Methods : Using an optomotor reflex test, rod-mediated contrast sensitivity was measured in dark-adapted P23H mice and littermate controls on a Gnat2^-/- background which blocks contribution of cone signals. Outer nuclear layer (ONL) thickness was compared between P23H mice and littermate controls with OCT. Rod sensitivity and rod-to-RBC inputs were measured in intact retinas with ex vivo ERG in 1-6 month-old P23H Gnat2^-/- double mutants and their littermate controls. We used pharmacology to identify possible mechanisms of compensation during ex vivo ERG recordings. Expression changes in plasticity-associated markers in P23H mice were measured by quantitative PCR from whole retina homogenates and from retinal cryosections by immunohistochemistry (IHC).

Results : P23H mice maintained nearly normal scotopic contrast sensitivity up to 5 months of age (P<0.05) despite ~70% thinning of the ONL. Rod and RBC light responses were progressively reduced in P23H mice as they aged. However, RBC responses were significantly sensitized to rod input based on the increased ratio of RBC and rod response amplitudes. Experiments with antagonists of inhibitory receptors (GABA, glycine and D2/4 receptors) did not have any significant effects on rod or RBC components of the ex vivo ERG. qPCR analysis from 1-month-old P23H mice revealed significant upregulation of Grm6 mRNA (P<0.05 vs. control) and modulation in the Slc-family of glutamate transporters. Conversely, IHC revealed progressively decreasing GRM6 positive puncta in P23H mice.

Conclusions : Our results suggest potentiated signal transmission in the rod-RBC synapse during rod degeneration. Results correlate with our optomotor experiments indicating that potentiation of rod-RBC signal transmission may partly explain the reasonably maintained scotopic vision despite advanced rod degeneration. Our results shed positive light in terms of vision restoration strategies in retinal blindness where positive neural remodeling could be a prerequisite for successful intervention.

This is a 2020 ARVO Annual Meeting abstract.