Asymmetrical ON/OFF retinal dysfunction in the mdx^Cv3 mouse model of Duchenne muscular dystrophy

Abstract

Purpose : The dystrophin mouse mutant mdx^Cv3 exhibits standard scotopic bright-flash electroretinogram (ERG) changes that most closely resemble those recorded from patients with Duchenne muscular dystrophy (DMD). We performed additional ERG paradigms on mdx^Cv3 mice under various conditions to study further parallels between the mdx^Cv3 line and human DMD.

Methods : Full-field ERGs (Q450 SC, Roland Consult) were recorded in anesthetized (Ket:Xyl, 60:5 mg/kg) mdx^Cv3 (n=9) and age-matched C57BL/6J wild-type littermates (n=10). Six stimulus protocols were presented: (i) inner retinal-dependent scotopic threshold responses (STR; -5.10 to -4.10 log scot cd.s/m²), (ii) rod scotopic flashes (-3.70 to 0.30 log phot cd.s/m²), (iii) cone photopic flashes (0.30 phot cd.s/m² flash on a 25 cd/m² background), (iv) sawtooth flicker eliciting mesopic ON- and Off-responses (1 cd/m², 4 Hz, 100% contrast), (v) long-flash stimulus for photopic ON-/OFF-responses (200 ms, 100 phot cd.s/m² on 60 cd/m²), and (vi) sinusoidal flicker stimuli (3–30 Hz, 60 cd/m², 100% contrast). Transient ERGs were analyzed in terms of their maximum and minimum component amplitudes and implicit times, while steady-state signals underwent Fourier analysis to extract amplitudes and phases of the fundamental component.

Results : The mdx^Cv3 mice exhibited smaller and slower scotopic ERGs (2-way RM-ANOVA, b-waves: up to -33%, +25±7 ms, oscillatory potentials: ≤-41%, +13±2 ms, all p<0.01) and smaller photopic ERGs (t-test, -28%, p=0.02) of similar timing. The downstream STR was not significantly affected. Interestingly, the timing (+25±4 ms, p<0.01), but not amplitude of the mesopic ON-response was affected, whereas both features were altered in the photopic ON-response (-41% and +14±10 ms, p≤0.04). In contrast, both mesopic and photopic OFF waves were within the norm. Sinusoidal flicker ERGs were altered in amplitude (-45%, p<0.01) but not in phase.

Conclusions : Scotopic, mesopic and photopic ERG changes in the mdx^Cv3 mice have been further defined. Like in DMD patients, dysfunction is likely restricted to the level of photoreceptor-to-bipolar cell transmission, where neural mechanisms required for mesopic/photopic vision, and ON-/OFF-processing are asymmetrically affected.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.