Abstract
Abstract: :
Purpose: Mutations in the NYX (nyctalopin) gene cause X–linked complete type congenital stationary night blindness (CSNB1). We used rapid–ON and rapid–OFF photopic flicker electroretinograms (ERGs) to evaluate ON– and OFF–pathway signaling in CSNB1 subjects and compared responses to monkey before and after suppressing ON– or OFF–pathway activity by intravitreal application of glutamate analogs. Methods: Rapid–ON and –OFF ramping flicker Ganzfeld photopic ERGs were elicited by 623 nm red stimuli (mean luminance of 4.1 log td at 90% modulation) on a 42 cd/m2 white background at 4–56 Hz. The same stimulus conditions were used throughout. Results: Rapid–on: Normal monkey and human response were nearly identical for both stimuli. CSNB1 and monkey after APB retained only the negative–going a–wave and lacked the b–wave. After PDA the monkey had a large positive–going waveform, quite unlike CSNB1. Rapid–off: The d–wave in CSNB1 was larger than normal human but otherwise similar. Surprisingly, after APB the monkey response was larger than control, indicating a considerable contribution from the ON–pathway to rapid–OFF flicker in primate. PDA eliminated the d–wave which was replaced by a negative–going response. APB + PDA together eliminated most of the response to both stimuli above 8 Hz, implying that photoreceptor contributions are minimal at higher frequencies. ON– and OFF–pathway activity: APB– and PDA–sensitive components in monkey were captured by waveform subtractions and compared with normal human and CSNB1. Normal human and monkey responses were essentially identical to each other for both stimuli. Suppressing DBC activity by APB in monkey gave a waveform that was remarkably similar to CSNB1 for both rapid–ON and –OFF stimuli. The leading edge of the PDA–sensitive (OFF–pathway) component corresponded with CSNB1. Eliminating the PDA–sensitive component in monkey gave a waveform quite dissimilar to CSNB1. Conclusions: Human CSNB1 responses were fully replicated in monkey after APB but not by PDA. This implicates specific signaling deficiency of the ON–pathway in CSNB1 with no apparent deficit in the OFF–pathway. These results support the proposition that nyctalopin acts principally or exclusively within the ON–pathway at the level of DBCs.
Keywords: electrophysiology: non–clinical • retina: proximal (bipolar, amacrine, and ganglion cells) • mutations