Neurochemistry Vol. I, pp. 69-80. Pergamon Press Ltd. |980. Printed in Great Britain.

ELECTROPHYSIOLOGICAL RESPONSES RELATED TO THE PIGMENT EPI- THELIUM AND ITS INTERACTION WITH THE RECEPTOR LAYER

S.E.G. Nilsson

Dept. of Ophthalmology, Univ. of LinkSping S-581 85 LinkSping, Sweden

ABSTRACT

The standin$ potential (SP) of the eye is generated mainly at the apical surface of the pigment epithelium, where tight junctions between adjacent cells create a high resistance membrane. It can be recorded indirectly by means of the electrooculo- gram (EOG) or directly by recording between electrodes connected to the cornea and the forehead. Changes in illumination provoke slow SP changes in the form of damped oscillations with a frequency of about 2/hour. These oscillations are abolished or substantially reduced in pigment epithelial diseases, such as retinitis pigmentosa and vitelline macular degeneration.

The c-wave of the electrOretinOgram (ERG) represents the hyperpolarization mainly of the apical membrane of the pigment epithelial cells that occurs in response to a decrease in potassium ion concentration in the extracellular space of the recep- tor layer induced by light stimulation. When repeatedly recorded the amplitude of the c-wave oscillated with time in the same way as the SP. The c-wave is abolished or markedly reduced in pigment epithelial disorders.

The negative h-wave of the off-ERG shows such extensive similarities to the c-wave of the on-ERG that it seems to represent the reversal of the processes in the pig- ment epithelium - receptor complex underlying the c-wave.

KEYWORDS

Retina; pigment epithelium; ocular electrophysiology; standing potential of the eye; electroretinography; c-wave; off-effects; animal experiments; clinical met- hods.

INTRODUCTION

When the retina is stimulated with light a series of biochemical and electrophy- siological reactions are initiated. Some of the electrical responses are generated in the neuroretina, whereas others are also closely related to the pigment epithe- lium, which interdigitates through processes with the retinal photoreceptor outer segments. The study of these responses has contributed to the basic understanding of the function of the retina and the pigment epithelium and the interaction bet-

69

70 S.E.C. Niisson

ween these two layers. Electrophysiological tests are also used in clinical oph- thalmology as valuable aids in the diagnosis of retinal and pigment epithelial di- seases.

THE STANDING POTENTIAL OF THE EYE

In vertebrates the cornea is positive in relation to the posterior pole of the eye. This potential difference is called the standing potential (SP) of the eye, discovered by du Bois-Reymond (1849). Experimental evidence indicated that the SP was generated mainly at the level of the pigment epithelium (Arden and Kelsey, 1962; Gouras, 1969; Heck and Papst, 1957; Noell, 1953, 1954). When advancing a microelectrode through the retina Brindley (1956) observed a layer of high elect- rical resistance, the R membrane. He proposed that the major part of the SP was generated across this membrane. The location of the R membrane was found to be be- hind the retina (Brindley and Hamasaki, 1963; Tomita, Murakami and Hashimoto, 1960% and Cohen (1965) proposed that the tight junctions (zonulae occludentes) between the pigment epithelial cells corresponded to the R membrane. It now seems gene- rally accepted that the apical surface (facing the photoreceptors) of the pigment epithelial cells together with the tight junctions constitute the morphological basis of the R membrane. The passive and active transport mechanisms related to this barrier were studied extensively by Steinberg and Miller (1973) and by Miller and Steinberg (1977 a, b).

The Electrooculosram (EOG)

SP variations can be recorded indirectly in human as the electrooculogram (EOG) by using a rather uncomplicated technique (Arden, Barrada and Kelsey, 1962; Francois, Verriest and de Rouck, 1955). The eye is rotated voluntarily from side to side at a certain angle. The potential variations created when the eye, being a dipole, is rotated like this, are picked up by electrodes at each canthus (Fig. i).

Recording is performed first in the dark and then in the light. Figure 2 shows that the potential variations decrease in the dark (dark trough) and increase in the light (light rise). The relation between the light rise and the dark trough (the 'Arden ratio') (Arden, Barrada and Kelsey, 1962), which is used in clinical tests, is pathologic in diseases affecting the pigment epithelium, e.g. in retinitis pig- mentosa (Fig. 3) and vitelline macular degeneration. The increase and decrease in the SP during EOG registration, initiated by turning on or off the light, respec- tively, were found to be cyclic and slow, about 2/h (Kolder, 1959; Kris, 1958; T~umer, Hennig and Pernice, 1974).

Direct SP Recordinss

A method for a more direct recording of the human SP between the cornea and the forehead, without using eye movements, was developed in our laboratory (Nilsson and Skoog, 1975; Skoog 1975). Very stable calomel electrodes were connected to a suction contact lens on the eye and to reference and ground chambers on the fore- head by saline-agar bridges in polyethylene tubes (Fig. 4). The signals were fed into low-drift d.c. amplifiers.

Eiectrophysiological Responses 7 1

Fig. i. Arrangement for EOG recording.

l i l i t l l tl ill I,,,;li li illiii • I11 II I II t! i it tl I~ t! I I i I II I II I : i ] ! ~ : ] ! i ! . . . . ]

Fig. 2. Normal human EOG. Arrows indicate turning off and on the adapting light, respectively. Time calibra- tion: I min intervals.

~, ÷

ill1 itl I~H i iLii~i~i m~i ii~JiJi IIITlrlilri1!fli!i111ili!I

i ] i i i i ! :: i i ! ~: ~ ~ i i I ~: i ; i

Fig. 3. 'Flat' EOG in retinitis pigmentosa.

72 S.E.G. Nilsson

Fig 4. Arrangement for direct SP registration.

d

ERG.__~ 0

VBA

YAp

sec

I0 mV

Fig. 8. Light evoked responses in the frog. Upper recording ERG recorded across a retina - pigment epithelium - choroid preparation (vitreal - positive). Middle recording: the pigment epithelial cell membrane po- tentials, recorded between an intracellular micro- electrode and either basal (VBA) or apical VAp) re- ference electrodes. Lower recording: differeh~ial potential from a double barrel K+-specific micro- electrode located approximately I0 ~m vitreal to the pigment epithelium. Reproduced from Oakley and co-workers (1977), with permission.

Electrophysiological Responses 73

4 -

light

min

Fig. 5. SP oscillations in response to a change in illumi- nation from darkness to 16 Lux. Reproduced from Skoog (1975), with permission.

mV

I ~ I I I I I - - 10

> rain

- - 1 ¸

Fig. 6. SP oscillations in response to a change in illumina- tion from ii00 Lux to darkness. Reproduced from Skoog (1975), with permission.

74 S.E.G. Ni±sson

Turning on the light after dark adaptation initiates slow and damped SP oscilla- tions with a frequency of about 2/h and with a maximum amplitude of approximately 5 mV (Skoog, 1975). A faster, negative transient precedes the slower changes, the first and major peak of which is positive (Fig. 5). A change from light to dark- ness provokes the same kind of SP oscillations, but with completely reversed po- larity (Fig. 6). Like the slow EOG variations also these SP oscillations are mar- kedly reduced or abolished in pigment epithelial diseases. Flashes of light (Nilsson and Skoog, 1975) and, unexpectedly, ethyl alcohol, taken orally (Skoog, Textorius and Nilsson, 1975), gave rise to the same type of response as turning on a steady light.

The mechanisms behind the SP oscillations are still unknown, but we suspect that metabolic processes in the pigment epithelium are involved. However, it seems that also factors outside the pigment epithelium influence upon the oscillations, since it has been shown (Textorius, Skoog and Nilsson, 1978) that experimental occlusion of the central retinal artery reduced markedly or abolished the light induced slow SP oscillations (Fi~. I0).

THE c-WAVE OF THE ELECTRORETINOGRAM (ERG)

The electroretino~ram (ERG) consists of a series of rather fast Dotential varia- tions, the most prominent of which are the negative a-wave and the positive b- and c-waves (Fi~. 7). These waves, which arise when the eye is stimulated with flashes of light, are superimposed upon the very much larger and slower SP variations. The a-wave reflects mainly the activity of the photoreceptor cells and the b-wave the computer part of the neuro-retina. The a- and b-waves are fast enough to be re- corded with the ordinary a.c. technique, but for the slower c-wave it is necessary to employ the more complex d.c. technique (Nilsson and Skoog, 1975).

m fill

Fig. 7. The d.c. recorded human ERG in response to a i sec stimulus. Stimulus intensity 4.5 log rel. units above b-wave threshold. Amplitude calibration i00 ~V.

Animal Experiments

The c-wave is generated primarily in the pigment epithelium and closely related a~ so to the activity of the photoreceptor cells. Noell (1954) demonstrated that the c-wave was abolished by sodium iodate. Light (Noell, 1954) and electron (Grignolo,

Electrophysiological Responses 75

Orzalesi and Calabria, 196~ microscopy showed that the pigment epithelium was da- maged by sodium iodate more than and prior to the neuroretina. Nilsson, Knave and Persson (1977 a, b) found that after sodium iodate injection there was definitely a period of time, when the c-wave was abolished and the pigment epithelium severe- ly damaged, but when the a- and b-waves were still unaffected and the neuroretina ultrastructurally normal. Brown and Wiesel (196~demonstrated that the amplitude of the c-wave of the local ERG was maximal when the electrode was placed adjacent to the pigment epithelium.

Steinberg, Schmidt and Brown (1970) and Schmidt and Steinberg (1971) showed that the intracellular response from the pigment epithelium was rod-dependent and iden- tical to the c-wave of the local ERG. It was found by Oakley and Green (1976) that light induced a decrease in extracellular potassium ion concentration in the recep- tor layer, and that this decrease had the same time course as the c-wave of the ERG. In experiments on the frog Oakley and co-workers (1977) and Oakley (1977) could demonstrate that simultaneously with the c-wave and the decrease in extra- cellular potassium the apical as well as the basal membrane of the pigment epithe- lial cells hyperpolarized, but the apical one significantly more than the basal one, and that this difference in hyperpolarization between the two membranes cor- responded in amplitude to the c-wave of the ERG (Fig. 8).

It thus appears that absorption of photons by the rods leads to a movement of po- tassium ions from the extracellular space, probably into the rods, and that this decrease in potassium causes a hyperpolarization mainly of the apical membrane of the pigment epithelial cells, which is recorded as the c-wave of the ERG.

Other slow potentials, simultaneous with the c-wave, such as slow P III (Granit, 1947; Noell, 1953, 1954), generated proximal to the receptor layer (Hanitsch, 1973; Murakami and Kaneko, 1966; Murakami and Sasaki, 1968; Pautler, Murakami and Nosaki, 1968), most likely ~y a MHller cell response to the earlier mentioned decrease in extracellular potassium ion concentration (Oakley, 1977; Witkovsky, Dudek and Ripps, 1975) may modify the positive c-wave, however (Faber, 1969; Oakley 1977; Rodieck, 1972). In studies by Textorius (1978), Textorius, Nilsson and Skoog (1978) and by Textorius, Skoog and Nilsson (1978) it was shown that occlusion of the cent- ral retinal artery, supplying the inner retina, caused a decrease in c-wave ampli- tude, slight but significant at the early stage, and markedly at the late stages (Fig. I0). These findings were surprising and further complicate the full under- standing of the c-wave. The ion fluxes through the retina may be altered.

The c-wave of the Human ERG

The human c-wave (Fig. 7) has been studied in detail in our laboratory as to metho- dological development (Nilsson and Knave, 1974; Nilsson and 8koog, 1975), ampli- tude and stimulus intensity relations (Skoog and Nilsson, 1974 a) and disturbances caused by superimposed off-potentials (Textorius, 1977). Furthermore, it was shown that the amplitude of the human c-wave, when repeatedly recorded, oscillated with time in the same way as the SP, i.e. with a frequency of approximately 2/h (Fig. 9) (Nilsson and Skoog, 1975, 1976; Skoog and Nilsson, 1974 b). These c-wave oscilla- tions were earlier observed also in animal experiments (Calissendorff, Knave and Persson, 1974; Knave and co-workers, 1973). Thus, one c-wave cannot be compared meaningfully to another c-wave, unless both are taken from identical phases of the oscillations. Many of the contradictory results in earlier reports may be explained by the fact that these amplitude oscillations were unknown (Textorius, Skoog and Nilsson, 1978).

76 S.E.G. Nilsson

mV

0,4

o,2

rain

Fig. 9. Slow cyclic changes of the amplitude of the c-wave of the human ERG on repeated stimulations and re- gistrations. Reproduced from Skoog and Nilsson (1974), with permission.

Like the SP oscillations also the c-wave amplitude oscillations were abolished in experimental occlusion of the central retinal artery (Textorius, Skoog and Nilsson, 1978) (Fig. i0). Ingestion of ethyl alcohol provoked oscillations of the c-wave amplitude of the same type as those induced by light flashes, although larger in

Fig. I0. Variations in the SP and the c-wave amplitude with time in response to repeated light stimuli (i sti- mulus per min) at a late stage (35 days) of occlu- sion of the central retinal artery (upper trace) and in the healthy control eye (lower trace). ERG:s mainly seen as c-waves, superimposed upon the SP traces. Stimulus duration 1 sec. Stimulus intensi- ty 45 cd/m 2. Reproduced from Textorius, Skoog and Nilsson (1978), with permission.

Electrophysiological Responses 77

magnitude (Skoog, 1974). Thus, many of the characteristics of the c-wave are also typical of the SP, which shows that the two potentials are closely related to each other and to the pigment epithelium. Furthermore, it has been shown in animal ex- periments that c-wave amplitude oscillations were elicited also by a number of drugs with melanin affinity, such as chloroquine (Calissendorff, 1976; Knave and co-workers, 1973).

"l

Fig. Ii. The d.c. registered human ERG in vitelline macular degeneration. Stimulus duration 4 sec. Stimulus in- tensity 4.0 log rel. units above b-wave threshold. Amplitude calibration I00 ~V. Time calibration i sec.

In d.c. registrations of the ERG in clinical cases the c-wave is found to be mar- kedly reduced or abolished in for example retinitis pigmentosa and vitelline macu- lar degeneration (Fig. II). In the former case the a- and b-waves are not seen or are very small, whereas in the latter case they are normal or slightly reduced. The described electrophysiological tests: EOG, direct SP registration and d.c. ERG, have proved to be most valuable in the diagnosis of many diseases concerning the retina and the pigment epithelium, above all in children and in hereditary cases, where the ophthalmoscopic picture may be difficult to interpret.

THE h-WAVE OF THE OFF-ERG

The potential variations occurring in the human ERG after cessation of an adapting light (with a duration of 20 sec or more) were studied by Skoog, Welinder and Nilsson (1977). A series of waves appeared at 'Off': a fast positive d-wave and a fast negative f-wave were followed by a slower positive g-wave and a slow negative h-wave. The h-wave at 'off' showed the same time course as the c-wave at 'on'. The h-wave amplitude also oscillated with time when repeatedly recorded as responses to 'dark flashes' (Welinder, 1979) and after ingestion of ethyl alcohol (Nilsson, Skoog and Welinder, 1978; Skoog, Welinder and Nilsson, 1978). It is therefore sug- gested as a working hypothesis that the h-wave of the 'off-ERG' represents the re- versal of the processes generating the c-wave of the 'on-ERG', i.e. an increase of the potassium ion concentration in the extracellular space of the receptor layer upon cessation of light, in turn causing a depolarisation mainly of the apical membrane of the pigment epithelial cells. More basic work is needed before the h- wave can be tried in routine clinical tests, however.

78 S.E.G. Nilsson

g

d ; ~ ,.oll~,.%

f h J

i

Fig. 12. Off-responses of the human d.c. registered ERG after the termination of an illumination of 60 Lux. Average of two recordings. Amplitude calib- ration i00 ~V. Time calibration I sec. Repro- duced from Skoog, Welinder and Nilsson (1978), with permission.

The present paper described three potentials that are related to the activity of the pigment epithelium and its interaction with the retinal photoreceptors: the standing potential of the eye, the c-wave of the on-ERG and the h-wave of the off- ERG.

ACKNOWLEDGEMENT

These investigations were supported by grants from the Swedish Medical Research Council, Project No. 12X-734.

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