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C. M. Tosha, B. Chen, J. Ramirez, S. Nusinowitz; Electroretinographic (ERG) Responses to Fast Temporally-Modulated (FTM) Stimuli in Stargardt (STGD) Disease. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5576.
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© ARVO (1962-2015); The Authors (2016-present)
STGD patients and the STGD mouse model have consistent ERG changes when photoreceptors are "stressed" by fast repetitive light stimuli. These changes appear to be present even when ERG responses to slower temporal modulations are within normal limits, suggesting that the ftmERG may more readily detect panretinal dysfunction. We investigate how disruption of rod- and cone- signaling pathways, gap junctions, and modulation of the visual cycle affect the morphology of the ftmERG response to better understand the cause of the ERG changes seen in STGD.
Dark-adapted ERGs were obtained to blue flashes modulated at a temporal frequency of 15 Hz. Flash intensity was varied from -4.7 log cd-s/m2 to -0.2 log cd-s/m2, in steps of 0.10 log units. Rod- and cone- contributions to the 15Hz ERG were evaluated using mice with targeted deletion of the α-subunit of rod- and cone- transducin (GNAT 1 and GNAT2, respectively) and the cyclic nucleotide-gated channel subunit α3 (CNGA3). The contribution of gap junctions was investigated with the Connexin36-/- (Cx36) and Cx36-/-/Gnat2-/- double knockout mice. C57BL/6J c2J and BALB/cByJ mice, isogenic except for a variation in the Rpe65 gene known to slow photopigment regeneration, were used to investigate the contributions from the visual cycle. The same variant in the STGD mouse model was also studied.
The ABCA4 mouse consistently showed reduced ftmERG amplitudes and phase changes compared to control mice at all intensities, even when the responses to slower temporal modulation were the same or nearly so. Removal of the direct contribution from cones (GNAT2 and CNGA3) and their indirect contribution to the rod-pathway via Cx36 gap junctions, produced phase shifts and significantly reduced amplitudes, even for dim flashes presumed to reflect only rod function. Modulation of the visual cycle in WT and ABCA4 mice with the Rpe65 variant had no effects.
The ftmERG provides a reliable and sensitive methodology to detect panretinal dysfunction of both rod- and cone- mediated function in STGD even when standard ERG responses are normal. The underlying cause of the reduced ftmERG is not fully understood but appears attributable primarily to defective cone function even for stimuli designed to maximize rod contributions. The visual cycle appears not to be involved.
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