Abstract
Congenital stationary night blindness (CSNB) is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had “negative-type” mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX), causal to a different form of CSNB (RHO) or X-chromosome (NYX, CACNA1F) location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2) and affected (n = 2) retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC) for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas. Interestingly, RGS11 showed no labeling in the affected retina. Our results indicate involvement of a yet unknown gene in this canine model of complete CSNB.
Highlights
Vertebrate retinas have highly sensitive rods and less sensitive yet faster responding cones as the primary photoreceptors to detect light energy
In parallel with other ongoing studies, we found that expression of most bipolar cell markers was drastically reduced when the 2% PF stage of fixation was extended to 48 hrs or longer; this was the case of the samples from Japan that were shipped to the University of Pennsylvania in 2% PF
We found comparable labeling in the dendritic tips of BP cells between normal and affected retinas for mGluR6 (Fig 8), GNB3 which forms a complex with Goα to couple mGluR6 with TRPM1 channel in the ON-bipolar cells (Fig 8; [50]), RGS7, important in the development and function of the photoreceptorbipolar cell synapse (Fig 8;[58]), GPR179, an interacting partner of TRPM1 (Fig 8), and TRPM1, the end product of the mGluR6 cascade (Fig 8)
Summary
Vertebrate retinas have highly sensitive rods and less sensitive yet faster responding cones as the primary photoreceptors to detect light energy. The processing of this visual information into neural signals includes secondary (bipolar cells and horizontal processes) and tertiary retinal neurons (amacrine and retinal ganglion cells (RGCs)) before being transmitted to the brain, producing image-forming vision. While rods are for night vision, cones aid in daylight and color vision. The photoreceptors are depolarized and their membrane potential becomes more positive as glutamate is continuously released into synapses with bipolar cells. The photoreceptors are hyperpolarized and their membrane potential becomes more negative as glutamate release is suppressed
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