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1 Department of Ophthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, Ann Arbor, MI, USA
2 Department of Ophthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, Ann Arbor, MI, USA; National Institutes of Health, National Institute of Deafness and Communicative Disorders (NIDCD), Bethesda, MD, USA
3 Department of Ophthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, Ann Arbor, MI, USA; National Institutes of Health, National Eye Institute (NEI), Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: paulsieving{at}nei.nih.gov.
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 analogs 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-NYX 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 CSNB1-NYX human for sinusoidal stimulation. The results implicated a specific ON-pathway signaling deficiency in CSNB1-NYX males, with no evidence of an OFF-pathway signaling abnormality. Rapid-on/-off ramping stimuli, to elicit ON- or OFF-pathway activity, also indicated that the functional deficit was localized to the ON-pathway with no need to invoke an OFF-pathway deficit. 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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