Abstract
Purpose :
Patients with complete congenital stationary night blindness (CSNB) have normal light-adapted vision despite having a functionally silent ON retinal pathway. This pathway is fundamental for encoding light increments across a visual scene and functions in parallel with the OFF retinal pathway to encode for contrast perception. How suppression of the ON pathway contributes to dysfunction of OFF alpha retinal ganglion cells (RGCs) across light conditions remain unclear and is important to understand the retinal circuit alterations in CSNB. The goal of this work is to advance mechanistic understanding of how the OFF pathway operates without ON pathway input in a mouse model of complete CSNB, delineating the associated cellular and circuit mechanisms.
Methods :
We use correlated single cell patch-clamp electrophysiology and immunohistochemistry to assay alpha RGC subtypes in two knockout mouse models: Grm6 +/- (50% expression) and Grm6 -/- (0% expression). Our experiments are performed across different light conditions to isolate circuit inputs and compare RGC outputs between light conditions. We measure spike outputs, excitatory and inhibitory synaptic inputs, and intrinsic properties to assay physiology together with quantification of synaptic proteins across RGC types.
Results :
Despite similar retinal circuitry, the different OFF alpha RGC types have divergent response profiles when the ON pathway is suppressed. Interestingly, the alterations in the response profiles are also light-level dependent. One OFF type displays aberrant activity which is much more pronounced at dim light conditions. Intrinsic properties of RGCs could be contributing to the observed functional deficits.
Conclusions :
The finding that patients with complete CSNB can lack a functional ON pathway and still have normal vision in photopic conditions is confounding. The OFF pathway depends on the inhibitory ‘crossover’ input from the ON pathway to drive parallel information processing of visual features at dim to mesopic conditions, yet it appears there are compensatory circuit mechanisms that circumvent this need at photopic conditions. Our findings at the level of RGC output provide cell-type specific mechanisms that could be contributing towards this finding.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.