Retinal ON-pathway dysfunction is implicated in human complete-type congenital stationary night blindness (CSNB1), a Mendelian genetic condition that results from mutations in the NYX gene encoding the protein nyctalopin. We probed cone pathway dysfunction in four human genotyped CSNB1 affected males by electroretinogram (ERG) recordings elicited with photopic sinusoidal and rapid-ON/OFF-ramp flicker stimuli that are reputed to elicit ON/OFF-pathway activity selectively. Results were analyzed in relation to ERG abnormalities created in anesthetized non-human primates by intravitreal application of glutamate analogues that selectively suppress retinal ON- or OFF-pathway bipolar cell activity. 2-amino-4-phosphonobutyric acid (APB), which selectively blocks light responses of ON-pathway depolarizing bipolar cells, fully recreated the essential ERG abnormalities found for human CSNB1 under the condition that the OFF-pathway remained active. Both CSNB1-NFX humans and APB-treated monkey retina lacked the normal amplitude dip and the phase deflection that occurs in the fundamental component near 12 Hz for sinusoidal flicker stimuli. The OFF-pathway suppressing agent, cis-2,3-piperidine-dicarboxylic acid (PDA), gave results in monkey quite discordant to CSNBl human for sinusoidal stimulation. The results implicated a specific ON-pathway signaling deficiency in CSNB1-NYX males with no evidence of OFF-pathway involvement. Likewise, rapid-ON/OFF ramping stimuli also indicated that the functional deficit was localized to the ON pathway. Analysis of non-human primate retinal responses after drug application demonstrated a complexity to ON/OFF-pathway contributions to ramping ON/OFF ERG responses not previously anticipated. These results support the hypothesis that nyctalopin acts principally or exclusively within the ON pathway at the level of depolarizing bipolar cells, and thus human CSNB1-NYX subjects provide an opportunity to probe the primate visual system for consequences of ON-pathway deficits.
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