An overview of electroretinogram response components to incremental and decremental steps in L- and M-cone excitation was obtained in human observers, while varying the spatial properties of the stimulus. Responses to L- and M-cone stimuli of opposite polarity resembled each other, particularly within the central 35° of the retina. All amplitudes grew as stimulus size increased; however, earlier and later components of the On- and Off-responses showed differing degrees of dependency on stimulus size. Thus, they may reflect different proportions of responses originating in parvocellular (less stimulus size-dependent) and magnocellular (more stimulus size-dependent) streams.

We show that cone signals are less sensitive than rod ERGs to acute IOP challenge. Also, retinal signals are more sensitive than are cortical signals to IOP stress, suggesting that cortical processing may act to salvage reductions expected from attenuated retinal output.

When combined with the electroretinogram (ERG), the heterochromatic flicker photometry procedure allows an objective in vivo assessment of postreceptoral activity. Responses evoked at intermediate (approximately 12 Hz) and high (>30 Hz) temporal frequencies reflect the red-green cone opponent (possibly parvocellular) and the luminance (possibly magnocellular) responses, respectively. Previously, we found that cone-isolating stimuli at intermediate temporal frequencies elicited ERG responses with similar amplitudes and phases for different spatial arrangements of the stimuli, whereas response amplitudes at high temporal frequencies were positively correlated with stimulus size. The purpose of this study was to investigate whether the influence of stimulus size was confined to cone-isolating stimuli or whether it was a general feature of heterochromatic stimulation. Furthermore, we aimed to determine the smallest spatial extent for a significant response in the two postreceptoral mechanisms. Monocular ERGs were recorded to red-green counterphase modulated sinusoidal stimuli (mean luminance of 200 cd/m2) presented at 12 and 36 Hz at different stimulus sizes. At each stimulus condition, a series of ERGs were recorded with the red-contrast fraction (FR) [FR = CR/(CR + CR)] of the stimulus varying between 0.0 and 1.0. Response amplitudes at 36 Hz changed with FR for all subjects, exhibiting a V-shaped amplitude profile with a minimum close to the psychophysics-based isoluminance, where the ERG phase changed by 180°. As stimulus size decreased, the amplitudes to 36 Hz also decreased. In contrast, amplitudes and phases at 12 Hz generally were constant for all values of FR. These amplitudes were invariant to stimulus sizes larger than 10° but decreased with decreasing stimulus size below 10°. Phase also changed in this range. Thus, luminance pathway ERG responses (36 Hz) show direct dependency on stimulus size, whereas chromatic pathway responses (12 Hz) are independent of the stimulus size above 10°.

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...

Tsai TI, Atorf J, Neitz M, Neitz J, Kremers J. Rod-and cone-driven responses in mice expressing human L-cone pigment. J Neurophysiol 114: 2230 -2241, 2015. First published August 5, 2015 doi:10.1152/jn.00188.2015.-The mouse is commonly used for studying retinal processing, primarily because it is amenable to genetic manipulation. To accurately study photoreceptor driven signals in the healthy and diseased retina, it is of great importance to isolate the responses of single photoreceptor types. This is not easily achieved in mice because of the strong overlap of rod and M-cone absorption spectra (i.e., maxima at 498 and 508 nm, respectively). With a newly developed mouse model (Opn1lw LIAIS ) expressing a variant of the human L-cone pigment (561 nm) instead of the mouse M-opsin, the absorption spectra are substantially separated, allowing retinal physiology to be studied using silent substitution stimuli. Unlike conventional chromatic isolation methods, this spectral compensation approach can isolate single photoreceptor subtypes without changing the retinal adaptation. We measured flicker electroretinograms in these mutants under ketamine-xylazine sedation with double silent substitution (silent S-cone and either rod or M/L-cones) and obtained robust responses for both rods and (L-)cones. Small signals were yielded in wild-type mice, whereas heterozygotes exhibited responses that were generally intermediate to both. Fundamental response amplitudes and phase behaviors (as a function of temporal frequency) in all genotypes were largely similar. Surprisingly, isolated (L-)cone and rod response properties in the mutant strain were alike. Thus the LIAIS mouse warrants a more comprehensive in vivo assessment of photoreceptor subtype-specific physiology, because it overcomes the hindrance of overlapping spectral sensitivities present in the normal mouse. keywords electrophysiology; mouse; photoreceptors; silent substitution IN RECENT YEARS, THE MOUSE has been the mainstay model for studying the physiology of the retina and retinal diseases. In vivo studies of retinal electrophysiology can be achieved by electroretinography (ERG). This method is noninvasive and enables repeated measurements from the same animal. Recent developments in ERG recordings in humans have shown that ERGs not have only a clinical value but also may give information on information processing in major retinogeniculate pathways with relevance for basic visual neuroscience (Kremers and Link 2008;Kremers et al. 2010;Parry et al. 2012). This relevance was recently confirmed for the mouse (Allen et al. 2014). To be able to study retinal signal processing and its disease-related changes, it is of great importance to isolate the responses of single photoreceptor types and record the signals that each elicits downstream. Also, in other studies of the retinal physiology, isolation of photoreceptor responses may lead to a better understanding of the information processing in the retina and for associated visual functions (Brown et al. 2010(Brown et al. , 2...

The aim of the study is to determine whether dimethyl sulphoxide (DMSO), a common laboratory solvent, impacts retinal function. Long Evans rats (n = 17) were intravitreally injected with five different doses of DMSO representative of those reported in the literature and spanning over 3 log units of vitreal concentration (0.01-8%). Retinal function was evaluated 1 h after injection using electroretinograms, and the waveform was decomposed into outer (photoreceptor), middle (ON-bipolar cell) and inner retinal (amacrine and ganglion cell) components. DMSO induces a dose-dependent decrease in retinal function for concentrations of 0.6% or more which is retinal layer specific. The photoreceptors of the outer retina returned normal responses at all doses (P > 0.05), whereas the mid-retinal bipolar cell response showed dose-dependent losses ranging from 21 +/- 1 to 82 +/- 1% (0.6-8% DMSO; P < 0.05). In a similar dose-dependent fashion, the inner retinal response was also affected by DMSO (0.6-8%: 23 +/- 12 to 98 +/- 3% loss, P < 0.05). A single dose of DMSO < or =0.1% (2.96 x 10(-5) microM) may be safely used to dilute compounds injected into the vitreous of a rat eye. Higher doses produce short-term (at least 24 h) retinal dysfunction.

The electroretinogram is a widely used objective measure of visual function. The best characterised feature of the full-field dark-adapted flash ERG, is the earliest corneal negativity, the a-wave, which primarily reflects photoreceptoral responses. However, recent studies in humans and primates show that there are post-receptoral contributions to the a-wave. It is not clear if such contributions exist in the rat a-wave. We consider this issue in the rat a-wave, using intravitreal application of pharmacological agents that isolate post-receptoral ON-pathways and OFF-pathways. In anaesthetised adult long Evans rats, we show that the ON-pathway (2-amino-4-phosphonobutyric acid, APB sensitive) makes negligible contribution to the a-wave. In contrast, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) or PDA (cis-piperidine-2,3-dicarboxylic acid) sensitive mechanisms modify the a-wave in two ways. First, for bright luminous energies, OFF-pathway inhibition (CNQX or PDA) results in a 22% reduction to the early phase of the leading edge of the a-wave up to 14 ms. Second, OFF-pathway inhibition removed a corneal negativity that resides between the a-wave trough and the b-wave onset.

Employing the silent substitution method with stimuli of appropriate luminance on the LIAIS mouse (as on human observers) increases the specificity, robustness, and scope to which photoreceptor-driven responses can be reliably assayed compared to the standard photoreceptor isolation methods.