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Y. Sauve, G. Gilmour, S. Chen, S. Kuny, I. M. MacDonald, S. Mema; Severe Rod Functional Loss Precedes Cone Dysfunction in a Mouse Model of Age-related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2007;48(13):15. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
AMD is the leading cause of blindness in the North American elderly population. Recent availability of the ELOVL4 mouse model of AMD offers hope for understanding AMD etiology and developing treatments. We used electroretinogram (ERG) recordings to determine the progression of rod and cone dysfunction.
ELOVL4 mice and wildtype (WT) littermates (line 2 from Dr. K Zhang, Moran Eye Center, Utah) were studied at 9 and 12 months of age. Under xylazine-ketamine anesthesia, ERGs were recorded (Espion E2, Diagnosys LLC). In addition to standard intensity-response tests, two cone-specific tests were used: 1) Scotopic double-flash ERG in which an initial flash bleached the rods, leading to isolated cone responses to a second flash delivered 800 msec later; 2) Photopic flicker ERG in which a flickering light stimulus of constant intensity was presented at frequencies varying from 5hz to 45hz.
For scotopic intensity-responses in ELOVL4 mice, maximal mixed a- and b-wave amplitudes were reduced to the amplitude levels of the isolated scotopic cone responses obtained using a double flash protocol. Isolation of rod response by subtraction of the double flash isolated cone responses from the mixed responses showed persistence of rod b-waves, exceeding the 20 µV criterion amplitude only for intermediate intensities, i.e. saturation was reached before that in WT. Photopic intensity responses showed reduced maximal b-waves, compared with WT, reaching statistical significance only at 12 months of age. Flicker ERG showed reduced amplitude to 30 Hz and reduced critical fusion frequency reaching statistical significance also at the same age (down from 45 Hz in WT to 35 Hz in ELOVL4). Dark adaptation (recovery of a- and b-wave amplitudes following 10 minutes exposure at 30 cd/m2) revealed absence of rod contribution in the ELOVL4 when followed up to 30 minutes scotopic adaptation. Normalization of scotopic mixed a-waves showed progressively reduced leading edge slopes. For the 12-month time point, recordings from some retinas had to be excluded from our analysis because a-waves did not exceed the 20 µV criterion amplitudes.
Our results indicate that cone dysfunction is detectable only after severe loss of rod function. Furthermore, our results in the ELOVL4 mouse model suggest that the use of a double ERG protocol under scotopic adaptation might allow for the early detection of cone dysfunction in AMD.
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