Cone Electroretinogram Responses Research Articles

Retinal Degeneration Slow (RDS) Glycosylation Plays a Role in Cone Function and in the Regulation of RDS·ROM-1 Protein Complex Formation

The photoreceptor-specific glycoprotein retinal degeneration slow (RDS, also called PRPH2) is necessary for the formation of rod and cone outer segments. Mutations in RDS cause rod and cone-dominant retinal disease, and it is well established that both cell types have different requirements for RDS. However, the molecular mechanisms for this difference remain unclear. Although RDS glycosylation is highly conserved, previous studies have revealed no apparent function for the glycan in rods. In light of the highly conserved nature of RDS glycosylation, we hypothesized that it is important for RDS function in cones and could underlie part of the differential requirement for RDS in the two photoreceptor subtypes. We generated a knockin mouse expressing RDS without the N-glycosylation site (N229S). Normal levels of RDS and the unglycosylated RDS binding partner rod outer segment membrane protein 1 (ROM-1) were found in N229S retinas. However, cone electroretinogram responses were decreased by 40% at 6 months of age. Because cones make up only 3-5% of photoreceptors in the wild-type background, N229S mice were crossed into the nrl(-/-) background (in which all rods are converted to cone-like cells) for biochemical analysis. In N229S/nrl(-/-) retinas, RDS and ROM-1 levels were decreased by ~60% each. These data suggest that glycosylation of RDS is required for RDS function or stability in cones, a difference that may be due to extracellular versus intradiscal localization of the RDS glycan in cones versus rods.

Cone-Rod Dependence in the Rat Retina: Variation with the Rate of Rod Damage

To assess the effect of accelerated rod damage on the integrity of cones in the rat retina. Rhodopsin-mutant P23H-3 and Sprague-Dawley (SD) rats were raised in scotopic ambient conditions (12 hours dark, 12 hours 5 lux) and then exposed to photopic conditions (12 hours dark, 12 hours 300 lux). Rods and cones were assessed for cell death, outer segment (OS) morphology, and electroretinogram (ERG) responses. Cones in the P23H-retina were affected rapidly by photopic exposure. Exposure for 2 days caused 50% reductions in LM- and S-cone OS length and cone ERG responses, associated with and preceded by reductions in rod OS length and ERG responses. Although 2 days' exposure increased the rate of rod death, outer nuclear layer thinning was minimal, and no evidence of cone death was detected. In the SD retina, the same photopic exposure had no measurable effects on death rates, OS length, or ERG responses in either rods or cones. Longer (7 days) photopic exposure reduced cone and rod OS length and ERG responses in SD, as well as P23H-3 retinas, but less severely than in the P23H-3 strain. Cones are damaged rapidly in the P23H-3 retina when rod damage is accelerated by raised ambient illumination. This close dependence of cone integrity on rod integrity contrasts with the life-long persistence of cone function in the scotopic reared P23H-3 rat. In humans suffering comparable photoreceptor dystrophies, the maintenance of steady, low ambient light may, by minimizing acute rod damage, optimize the function of surviving cones.

Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase.

Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate the essential role of AIPL1 in retina, we generated a mouse model of LCA by inactivating the Aipl1 gene. In Aipl1(-/-) retinas, the outer nuclear layer develops normally, but rods and cones then quickly degenerate. Aipl1(-/-) mice have highly disorganized, short, fragmented photoreceptor outer segments and lack both rod and cone electroretinogram responses. Recent biochemical evidence indicates that AIPL1 can enhance protein farnesylation. Our study reveals that rod cGMP phosphodiesterase, a farnesylated protein, is absent and cGMP levels are elevated in AIPL1(-/-) retinas before the onset of degeneration. Our findings demonstrate that AIPL1 enhances the stability of phosphodiesterase and is essential for photoreceptor viability.

Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations

PurposeTo present long-term follow-up on a North American patient with Leber congenital amaurosis (LCA) and novel compound heterozygous mutations in the RPE65 gene. DesignCase report. MethodsRPE65 mutation screening and search for sequence changes using Single Strand Conformation Polymorphism and direct DNA sequencing. Ophthalmic examination and electrophysiologic testing. ResultsA 35-year-old female carried two RPE65 mutations: a maternal 961A>T (K303X) nonsense mutation and a paternal 1346A>G (Y431C) missense mutation. She had severe visual deficits and an absence of rod and cone Electroretinogram responses. Visual acuity of 20/60 both eyes and normal color recognition during early childhood declined to 2/200 in the right eye and 1/200 in the left eye at the age of 35. ConclusionsThe RPE65 mutations K303X and Y431C in compound heterozygous form cause progressive visual compromise that starts in childhood and advances to severe visual loss by the fourth decade of life.

A comparison of three techniques to estimate the human dark-adapted cone electroretinogram

The dark-adapted cone electroretinogram (ERG) is difficult to isolate because of unwanted rod intrusion. We compare dark-adapted cone estimates derived using three techniques. The first uses the cone response on a moderate rod saturating background to estimate the dark-adapted cone response. The second uses red and blue flashes to tease apart cone and rod responses (red-minus-blue technique, [Investigative Ophthalmology and Visual Science 31 (1990) 2283]). The third uses a bright flash to temporarily saturate rods, followed by a test flash that generates a putative cone-only response (2-flash technique [Investigative Ophthalmology and Visual Science 36 (1995) 1603]). By subtracting the cone estimates from ‘mixed’ ERG responses in the dark, rod isolated responses can be derived. The rod phototransduction parameters, derived using a computational model, are similar using the light-adapted and 2-flash cone estimates, but differ using the red-minus-blue estimates. The 2-flash cone estimate gives a cone waveform similar to the dark-adapted response of a patient with Oguchi stationary night blindness (a patient with no rod ERG responses and normal cone ERG responses). The growth of the cone response during light adaptation to steady backgrounds causes significant differences between the light-adapted and 2-flash cone waveforms at times beyond the first few milliseconds.

Detection using the multifocal electroretinogram of mosaic retinal dysfunction in carriers of X-linked retinitis pigmentosa

PurposeTo examine whether a mosaic pattern of retinal dysfunction in obligate carriers of X-linked retinitis pigmentosa (XLRP) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG). DesignProspective observational case series. ParticipantsFive obligate carriers of XLRP (mean age, 53.2 years) were recruited into the study. MethodsExamination of each subject included a complete ocular examination, Humphrey visual field, standard full-field electroretinogram (ERG), and mfERG testing. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40° in diameter. The amplitudes and implicit times in each location for the mfERG was compared with the corresponding value determined for a group of normally sighted, age-corrected control subjects. Main outcome measuresMapping of 103 local electroretinographic response amplitudes and implicit times within the central 40° with the multifocal electroretinogram. ResultsLocalized regions of reduced mfERG amplitudes and/or delayed implicit times were found in four of five carriers. In one of these four carriers, a mosaic pattern of mfERG dysfunction was present even in the absence of any clinically apparent retinal changes, retinal sensitivity losses on Humphrey field testing, or abnormal full-field cone ERG responses. However, one carrier with a typical tapetal-like reflex demonstrated no deficit on any functional tests. ConclusionsThe mfERG demonstrated patchy areas of retinal dysfunction in some carriers of XLRP. This mosaic pattern of dysfunction may be observed in some patients with a normal-appearing fundus, normal psychophysical thresholds, and normal amplitude and implicit time full-field ERG cone responses.

Foveal Cone Dysfunction Syndrome

Our objective was to describe and expand the clinical spectrum of a rarely detected, previously reported photoreceptor disorder restricted to the foveal cones. Three patients with bilaterally decreased acuity and hemeralopia were examined to exclude a structural, vascular, inflammatory, or degenerative process. Each patient underwent a full neuroophthalmic examination, including full-field and focal cone electroretinogram (ERG). All three patients had normal-appearing fundi, mild dyschromatopsia, central or paracentral visual field depressions, normal full-field photopic and scotopic ERGs, and markedly reduced focal, foveal cone ERG responses. One patient had a ring scotoma and an asymptomatic family member with abnormal full-field and focal cone ERG. The syndrome of acquired foveal cone dysfunction presents as a bilateral, painless, progressive central visual loss with minimal or absent fundus changes. It eludes diagnosis until focal, foveal cone ERG is performed.

Reduced blue cone electroretinogram in withdrawn cocaine dependent patients: A replication

The electroretinogram (ERG) is a neurophysiologic technique for recording electric potentials from the retina in response to a flash of light. We previously compared 20 recently withdrawn cocaine dependent patients with 20 matched normal controls for responses of their retinal cone and rod photoreceptors to light flashes on full-field ERG (Roy et al 1997b). We reported that the cocaine withdrawn patients had significantly reduced mean blue cone ERG responses compared to controls. We wished to try and replicate this finding.

Rapid and slow changes in the human cone electroretinogram during light and dark adaptation

Changes in the response characteristics of the human cone electroretinogram (ERG) during light and dark adaptation were studied in two visually normal subjects. Cone ERG responses were isolated under all adaptation conditions through the use of 31 Hz flicker. To determine the time-course of changes in the cone ERG during adaptation, responses to stimuli of constant luminance were measured repeatedly during 15 min of exposure to an adapting field of 2.0 log cd/m2 and during 30 min of dark adaptation following adapting field termination. In addition, luminance-response functions were obtained before and immediately after adapting field onset, as well as before and immediately after adapting field termination. The results indicate that the human cone ERG is influenced by two major processes. One process has a relatively rapid time-course and serves to reposition the luminance-response function along the luminance axis following changes in ambient light levels. The second process, which has a slow time-course, scales response amplitudes during light and dark adaptation by the same proportion at all stimulus luminances. The results provide a framework for predicting the manner in which the cone ERG will change with alterations in the state of retinal adaptation.

Rod responses in retinitis pigmentosa, dominantly inherited.

Psychophysical and electrophysiological methods are used to evaluate retinal function in a family with dominantly inherited retinitis pigmentosa. Techniques of full-field (ganzfeld) stimulation, scotopically balanced lights, and a ganzfeld adapting field are introduced to analyze the electroretinogram (ERG). Rod ERG responses, reduced in amplitude and delayed in latency, are detectable in the early stages of the disease. Cone ERG responses are normal. Dark adaptation testing shows normal cone but abnormal rod function with a slight delay in the rate of rod recovery. Scotopic luminosity curves and ERG responses to scotopically matched lights suggest that the rhodopsin present has a normal absorption spectrum. A reduction in the amount or effectiveness of rhodopsin in each rod throughout the entire retina can explain the findings. The literature on light-induced retinal degenerations is reviewed, and the effects of light exclusion on this disease are considered.