Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

The purpose of this study was to determine what contributions are made to the rat full-field electroretinogram (ERG) by ganglion cells (GCs). To that end, the ERG was assessed longitudinally following optic nerve transection (ONTx). Additional studies were conducted using intravitreal injections of pharmacologically active substances. The ERG was recorded simultaneously from both eyes of anaesthetized adult Brown-Norway rats (ketamine: xylazine: acepromazine, 55: 5: 1 mg kg(-1)) using custom silver chloride electrodes. Stimuli were brief, white xenon discharges delivered via a Ganzfeld under dark-adapted and light-adapted conditions (150 cd m(-2)). ERGs were obtained 1, 2, 3, 4 and 9 weeks after ONTx (n = 8) or sham (n = 8) operations. ONTx reduced both positive and negative components of the scotopic threshold response (pSTR and nSTR). Scotopic ERG responses to brighter flashes, including a-waves, b-waves and oscillatory potentials (OPs) were unaffected by ONTx. ONTx reduced the photopic b-wave and OPs. TTX (6 microM) reduced the pSTR and nSTR, but not the scotopic a-wave, b-wave or OPs. TTX had dramatic effects on the photopic ERG, surpassing the effects of ONTx. TTX application 9 weeks post-ONTx had little additional effect on the STR. Inhibition of inner retinal responses using GABA (10 mM) or NMDA (0.8 mM) reduced the nSTR substantially. Similar results were obtained with antagonists of AMPA/KA ionotropic glutamate receptors 6-cyano-7-nitroquinoxaline-2,3(1H,4H)-dione (CNQX, 0.2 mM) or cis-2,3-piperidinedicarboxylic acid (PDA, 5 mm); however, both also reduced the scotopic b-wave by approximately 40 %. By contrast, the NMDA receptor antagonist D(-)-2-amino-7-phosphonoheptanoic acid (D-AP7, 0.2 mM) had no effect alone, but the combination of D-AP7 and CNQX completely abolished the STR. The results of this study indicate that: (1) both pSTR and nSTR components in the rat depend directly upon intact GC responses, and that amacrine cell contributions to these components are relatively small; (2) scotopic ERG response components to brighter flashes receive little influence from GCs; (3) the rat photopic ERG also reflects GC signals and may serve as an additional useful test of GC function; (4) TTX had dramatic effects on the rat photopic ERG that were not attributable to GC currents, but rather to voltage-gated sodium currents in amacrine or interplexiform cells; (5) a small residual negative STR persisted after ONTx that was likely to be generated by graded responses of third-order retinal cells, most likely amacrine cells.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2003.052738

Ganglion cell contributions to the rat full-field electroretinogram.

The purpose of this study was to determine what contributions are made to the rat full‐field electroretinogram (ERG) by ganglion cells (GCs). To that end, the ERG was assessed longitudinally following optic nerve transection (ONTx). Additional studies were conducted using intravitreal injections of pharmacologically active substances. The ERG was recorded simultaneously from both eyes of anaesthetized adult Brown‐Norway rats (ketamine: xylazine: acepromazine, 55: 5: 1 mg kg−1) using custom silver chloride electrodes. Stimuli were brief, white xenon discharges delivered via a Ganzfeld under dark‐adapted and light‐adapted conditions (150 cd m−2). ERGs were obtained 1, 2, 3, 4 and 9 weeks after ONTx (n= 8) or sham (n= 8) operations. ONTx reduced both positive and negative components of the scotopic threshold response (pSTR and nSTR). Scotopic ERG responses to brighter flashes, including a‐waves, b‐waves and oscillatory potentials (OPs) were unaffected by ONTx. ONTx reduced the photopic b‐wave and OPs. TTX (6 μm) reduced the pSTR and nSTR, but not the scotopic a‐wave, b‐wave or OPs. TTX had dramatic effects on the photopic ERG, surpassing the effects of ONTx. TTX application 9 weeks post‐ONTx had little additional effect on the STR. Inhibition of inner retinal responses using GABA (10 mm) or NMDA (0.8 mm) reduced the nSTR substantially. Similar results were obtained with antagonists of AMPA/KA ionotropic glutamate receptors 6‐cyano‐7‐nitroquinoxaline‐2,3(1H,4H)‐dione (CNQX, 0.2 mm) or cis‐2,3‐piperidinedicarboxylic acid (PDA, 5 mm); however, both also reduced the scotopic b‐wave by ∼40 %. By contrast, the NMDA receptor antagonist D(‐)‐2‐amino‐7‐phosphonoheptanoic acid (D‐AP7, 0.2 mm) had no effect alone, but the combination of D‐AP7 and CNQX completely abolished the STR. The results of this study indicate that: (1) both pSTR and nSTR components in the rat depend directly upon intact GC responses, and that amacrine cell contributions to these components are relatively small; (2) scotopic ERG response components to brighter flashes receive little influence from GCs; (3) the rat photopic ERG also reflects GC signals and may serve as an additional useful test of GC function; (4) TTX had dramatic effects on the rat photopic ERG that were not attributable to GC currents, but rather to voltage‐gated sodium currents in amacrine or interplexiform cells; (5) a small residual negative STR persisted after ONTx that was likely to be generated by graded responses of third‐order retinal cells, most likely amacrine cells.

Ganglion Cell Contribution to the Rat Full Field Electroretinogram

We have developed an electronic spatial frequency sweep technique for electrophysiological assessment of visual acuity and pattern vision. The technique allows an accurate and reliable measurement of VEPs to a full range of spatial frequencies in just 10 sec. Because the measurements are so rapid, the technique suggests several new improvements in the assessment of visual function. Sweeping spatial frequency linearly and extrapolating the high-frequency region of the VEP spatial-tuning function to zero voltage allows an estimate of acuity which correlates highly with psychophysical estimates of acuity. Variants of the procedure are appropriate for the assessment of refracture error, determination of equality of visual function for the two eyes and of binocular interactions, and for sequential assessment of therapeutic conditions.

/pdf/rapid-assessment-of-visual-function-an-electronic-sweep-2iimr84aje.pdf

Rapid assessment of visual function: an electronic sweep technique for the pattern visual evoked potential.

In mammals, the pupillary light reflex is mediated by intrinsically photosensitive melanopsin-containing retinal ganglion cells that also receive input from rod-cone photoreceptors. To assess the relative contribution of melanopsin and rod-cone photoreceptors to the pupillary light reflex in humans, we compared pupillary light responses in normally sighted individuals (n=24) with a blind individual lacking rod-cone function. Here, we show that visual photoreceptors are required for normal pupillary responses to continuous light exposure at low irradiance levels, and for sustained pupillary constriction during exposure to light in the long-wavelength portion of the visual spectrum. In the absence of rod-cone function, pupillomotor responses are slow and sustained, and cannot track intermittent light stimuli, suggesting that rods/cones are required for encoding fast modulations in light intensity. In sighted individuals, papillary constriction decreased monotonically for at least 30 min during exposure to continuous low-irradiance light, indicating that steady-state pupillary responses are an order of magnitude slower than previously reported. Exposure to low-irradiance intermittent green light (543 nm; 0.1-4 Hz) for 30 min, which was given to activate cone photoreceptors repeatedly, elicited sustained pupillary constriction responses that were more than twice as great compared with exposure to continuous green light. Our findings demonstrate nonredundant roles for rod-cone photoreceptors and melanopsin in mediating pupillary responses to continuous light. Moreover, our results suggest that it might be possible to enhance nonvisual light responses to low-irradiance exposures by using intermittent light to activate cone photoreceptors repeatedly in humans. Â© 2012 the authors.

https://www.jneurosci.org/content/jneuro/32/41/14242.full.pdf

Melanopsin and Rod–Cone Photoreceptors Play Different Roles in Mediating Pupillary Light Responses during Exposure to Continuous Light in Humans

PURPOSE. To determine whether the photopic negative response (PhNR) of the electroretinogram (ERG) is reduced in patients with primary open angle glaucoma (POAG). METHODS. ERGs were recorded with DTL electrodes from 62 normal subjects (16 to 82 years), 18 POAG patients (47 to 83 years) and 7 POAG suspects (46 to 73 years) to brief flashes (<6 ms), and also in a few subjects to long (200 ms) red, full-field ganzfeld flashes delivered on a rod-saturating blue background. At the time of ERG measurements, the intraocular pressures of most of the patients were controlled medically. Visual field sensitivities were measured with the Humphrey C24-2 threshold test and optic nerve head cup-to-disc ratio (C/D) was determined by binocular indirect ophthalmoscopy. RESULTS. ERGs of normal subjects contained a slow negative potential following the a- and b-waves, the PhNR, that increased slightly in latency with age. The a- and b-wave amplitudes and implicit times of POAG patients were similar to age-matched controls. In contrast, their PhNRs were small or virtually absent. PhNR amplitudes were reduced even when visual sensitivity losses were small, and were correlated significantly (P < 0.05) with mean deviation (MD), corrected pattern SD (CPSD), and C/D across the population of POAG patients whose MD losses ranged from 1 to 13 dB, CPSDs from 0 to 11 dB and C/Ds from 0.6 to 0.9. PhNRs of most POAG suspects also were small. CONCLUSIONS. PhNR amplitudes in POAG patients are smaller than those of normal subjects. PhNR amplitudes are reduced when visual field sensitivity losses are mild and become even smaller as sensitivity losses increase. There is a potential role for the PhNR in early detection and possibly in monitoring the progression of glaucomatous damage.

The photopic negative response of the flash electroretinogram in primary open angle glaucoma.

Sinusoidally modulated checker board patterns were used to investigate the effects of check size and retinal location on the "steady-state" visual evoked response (VER) of strabismic and anisometropic amblyopes. Fourier analysis of the averaged VER suggests that the waveforms produced by these techniques are complex, and that they consist of a fundamental component plus 1 or more harmonics. In all of the subjects, the VERs elicited from the amblyopic eyes by small checks in a 3.5-deg disc were significantly smaller in amplitude than those from the nonamblyopic eyes, whereas the responses to larger checks were far more similar. Large annular targets were quite effective in eliciting VERs from the peripheries of both amblyopic and nonamblyopic eyes, and these responses were at times as large as, or larger than, those produced by the central targets. Statistically no significant differences were found between the responses of the amblyopic and the nonamblyopic eyes to the annular targets.

Visual evoked responses in strabismic and anisometropic amblyopia: effects of check size and retinal locus.

Background: Autosomal dominant optic atrophy (ADOA, Kjer-type) is a heterogeneous, non-inflammatory degeneration of retinal ganglion cells. The diagnosis of ADOA can be challenging owing to its insidious onset and large variability in phenotypic expression, both within and between individual pedigrees. The earliest literature reports relatively mild centrocaecal scatomas to white targets in ADOA, but extensive and dense peripheral field loss to coloured targets, especially blue, with Bjerrum perimetry. The phrase “inverted peripheral visual fields to coloured targets” has been used to describe this phenomenon. Methods: Humphrey standard achromatic perimetry (SAP) and short wavelength-automated perimetry (SWAP) were carried out on five patients with ADOA. Results: Regardless of wide variations in patient age, visual acuity, disc appearance and colour vision, the SWAP mean deviation (MD) was between 10 and 20 times more depressed than the SAP MD. The actual differences ranged from 9.38 to 13.78 dB. Conclusions: These data are consistent with the original reports suggesting that, early in this disease process, the blue-target deficits are typically peripheral and that this difference between SAP and SWAP perimetry may be a robust indicator of ADOA in both early and late stages of this disease.

/pdf/short-wavelength-automated-perimetry-compared-with-standard-1n1o3pgvrm.pdf

Short wavelength-automated perimetry compared with standard achromatic perimetry in autosomal dominant optic atrophy.

The mechanism of brightness enhancement

Between 1977 and 1980, several teams of faculty and students from the University of Houston College of Optometry examined in excess of 2,200 children and young adults from schools for the deaf in the states of Arkansas, Missouri, Louisiana, and Texas. Routine tests and procedures included tests for visual acuity, peripheral vision, pupillary reflexes, ocular motor function, color vision, intraocular pressure, and refractive error as well as a careful examination of ocular structure with biomicroscopy and ophthalmoscopy. Additional testing done on-site on a referral basis included perimetry, electroretinography, and internal and external photography. It is the opinion of the authors that these data indicate a need for increased emphasis on the evaluation of vision function in schools for the deaf. We further believe this can be done on-site by appropriately trained existing staff working in conjunction with a carefully chosen mix of professional consultants.

James W. Walters

Papers

The photopic negative response of the flash electroretinogram in primary open angle glaucoma.

Visual evoked responses in strabismic and anisometropic amblyopia: effects of check size and retinal locus.

Short wavelength-automated perimetry compared with standard achromatic perimetry in autosomal dominant optic atrophy.

The mechanism of brightness enhancement

Vision: Its Assessment in School-Age Deaf Children