Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Abstract

Citation: Tsai TI, Barboni MTS, Nagy BV, et al. Asymmetrical functional deficits of ON and OFF retinal processing in the mdx 3Cv mouse model of Duchenne muscular dystrophy. Invest Ophthalmol Vis Sci. 2016;57:5788-5798. DOI:10.1167/ iovs.16-19432 PURPOSE. The dystrophin mouse mutant mdx 3Cv exhibits scotopic electroretinograpic (ERG) abnormalities, which resemble clinical changes observed in Duchenne muscular dystrophy (DMD) patients. In the present study, ERGs obtained from mdx 3Cv and their wild-type littermates under scotopic, mesopic, and photopic conditions were analyzed to provide further insight on the affected retinal pathways, and to compare them with human data. METHODS.Electroretinograms of mdx 3Cv (n ¼ 9) and age-matched C57BL/6J mice (n ¼ 10) included the scotopic full-field flash (for outer retinal deficits in rod pathway), scotopic threshold response (for inner retinal integrity), photopic flash, sinusoidal flicker (for outer retinal deficits in cone pathway), mesopic rapid-on/-off sawtooth flicker, and photopic longduration flash measurements (for separate ON-/OFF-responses under different conditions). RESULTS.The mdx 3Cv mice exhibited diminished and delayed scotopic and photopic ERGs, particularly in their b-wave and oscillatory potentials. Interestingly, homologues to the a-and b-wave of the mesopic ON-response were affected in their peak/trough times but not in their amplitude, whereas changes to both features were uncovered for photopic ON-response and sinusoidal flicker. Mesopic and photopic OFF-components were within the norm.CONCLUSIONS. Abnormal scotopic and photopic flash ERGs were observed in mdx 3Cv , which corroborate with deficits that are likely restricted to the level of photoreceptor-to-bipolar cell transmission. Further overlaps between mdx 3Cv mice and DMD patients exist, including asymmetrical ON versus OFF ERG alterations under mesopic versus photopic vision. In mice, ON-pathway function is compromised, whereas the OFF-pathway is spared.Keywords: Duchenne muscular dystrophy, dystrophin, electrophysiology, mouse model D ystrophin is a 427-kDa protein (Dp427), in which nonsense mutations in its gene (dmd) can cause Duchenne muscular dystrophy (DMD), a lethal, X-linked recessive muscle degenerative disease that primarily affects male children. 1 Shorter gene products of the protein, also transcribed by dmd, are present in different tissues.2 The retina, for example, is a tissue where extensive expressions of the dystrophin proteins occur. Besides Dp260, the predominant retinal gene products of dystrophin found in the outer plexiform layer (OPL), 3 the full protein Dp427, and shorter DMD gene products Dp140 and Dp71 are also found at various locations in the retina (reviewed in Ref. 4).Mouse strains lacking single or multiple dystrophin gene products have provided different models to study the mechanisms underlying electroretinographic (ERG) abnormalities in DMD patients. 5 Varying degrees of retinal dysfunction are associated with different dmd mutations. 6 Dp71, for example...

Electrodiagnosis of dichromacy

“…to L I /M D and to L D /M I ) because of the resemblance in the response waveforms. This was also found previously McKeefry et al, 2014;Tsai, Barboni, et al, 2016) and indicates the above-mentioned presence of cone opponency in the responses. Interestingly, the L-/M-ratio is what is expected from a luminance reflecting response because cone-opponent retinal pathways have a balanced input from L-and M-cones (Lee, 1996;Smith, Lee, Pokorny, Martin, & Valberg, 1992).…”

“…A Ganzfeld bowl (Q450SC; Roland Consult, Brandenburg, Germany) equipped with six arrays of differently colored light-emitting diodes (LEDs) was used as a stimulator. As previously described (Barboni et al, 2017;Kremers et al, 2014;Tsai, Barboni, et al, 2016), four LED arrays were used: red (peak wavelength ± half width at half maximum = 638 ± 9 nm), green (523 ± 19 nm), blue (469 ± 11 nm), and amber (594 ± 8 nm). The luminance of each LED array was modulated with rapid-on or rapid-off sawtooth profiles.…”

“…They are less burdening for the observers than long-flashes and thus less disturbed by blinks and squints. These electrophysiological protocols can be useful to evaluate asymmetrical impairment of ON-and OFF-post-receptoral visual pathways (Alexander, Barnes, Fishman, & Milam, 2002;Alexander, Fishman, Barnes, & Grover, 2001; Barboni et al, 2013;Pangeni, Lämmer, Tornow, Horn, & Kremers, 2012;Tsai, Barboni, et al, 2016). However, these signals are initiated by a combined and in-phase stimulation of all cone types.…”

“…The L-/M-opponency is also present in VEP responses (Barboni et al, 2017), pupillary reflexes (Murray, Kremers, McKeefry, & Parry, 2018;Woelders et al, 2018) and psychophysical data . Moreover, subjects with congenital color vision deficiencies show near to absent VEP and ERG responses when the absent cone type is selectively stimulated (Barboni et al, 2017;Kremers et al, 2014;McKeefry et al, 2014;Tsai, Barboni, et al, 2016).…”

Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy

“…As a matter of fact, some brain functions are decreased in animal models as the mdx 3 Cv mouse (X linked muscular dystrophy 3, Verne Chapman), a mdx mouse variant generated with N -ethylnitrosourea chemical mutagenesis and carrying a point mutation in intron 65 of the DMD gene, which abrogates the expression of all shorter dystrophin isoforms ( Im et al, 1996 ; Willmann et al, 2009 ). Similar considerations can be drawn for the aforementioned visual defects ( Tsai et al, 2016 ), which are either absent or less severe in mdx mice compared to DMD patients and mdx 3 Cv mice ( Costa et al, 2007 ; Costa et al, 2011 ; Tsai et al, 2016 ; Bucher et al, 2019 ). However, upstream to all these considerations is the developmental manifestation of the dystrophin isoforms in the nervous system, which can vary among species, and their co-expression with genes implicated in neurodevelopmental disorders ( Doorenweerd et al, 2017 ).…”