Visual Function in a Mouse Model of Stargardt-like Dystrophy (STGD3)

Abstract

Purpose: : To characterize visual function in a mouse model of STGD3 using head turning testing and to examine the corresponding retina function and anatomy in the same animals.

Methods: : Optokinetic responses (OKR) to moving sine-wave gratings were tested in a virtual optomotor apparatus. ELOVL4-line2 mice (E4, n=3) and wild-type (WT n=3) C57/BL6 littermates (from Dr. Zhang) were tested at 9 months of age. Horizontally rotating sine-wave gratings of various contrasts (0-93%), spatial frequencies (SF = 0.025 c/d to 1.4 c/d) and drift speeds (6, 12, 24 d/s), evoked head following-movements, by which an observer blind to the genotypes, determined OKR contrast threshold (CT) and contrast sensitivity (CS). Mice were then submitted to electroretinogram (ERG) recordings and retina anatomical investigations.

Results: : The optokinetic responses of all mice were most sensitive to gratings drifting at V=12 d/s. WT responded robustly, with maximal CS ~12.5 (CT ~8% contrast) and maximal CS constant at spatial frequencies (SF)=0.08-0.3 c/d. The CS function showed a sharp high-SF cut-off, reaching a minimum at SF=0.55-0.6 c/d (acuity). Two E4 (#1 and #2) were poorly responsive to the visual approach of the experimenter and required more time than WT to attend to the grating and perform reliably. These animals had optimal CS ~2.5 and 9 (CT ~40% and 11% contrast, respectively) at 0.1 c/d, and acuity=0.35 c/d. E4 mice #1 and #2 had severely compromised ERGs and reduced photoreceptor numbers. E4 mouse #3 behaved as WT with similar contrast and acuity resolution. In addition, ERG and anatomical findings correlated with both of these OKN parameters for that very animal despite unambiguous genotyping as E4.

Conclusions: : The variability in E4 observed at 9 months of age, from normal to almost blind (such as reduced CS, acuity, ERG amplitudes, and number of photoreceptors), can be attributed to the expression level of the transgene. The variability observed at this age (as opposed to older ages) provides a unique opportunity for correlative studies addressing how, 1) the degeneration of specific retina cell types and their center to periphery localization in the retina, 2) specific ERG parameters and, 3) psychophysical parameters measured behaviourally, all relate with each other.

Keywords: degenerations/dystrophies • visual acuity • electrophysiology: non-clinical