Feedback connections plexiform

and operation

of the outer

layer of the retina

Samuel M. Wu Baylor College of Medicine,

The

primary

feedback

control

apparatus

sign-inverting

feedback

synapse

between

many

lower

opens

Cl-

synapse

vertebrates channels

reveal that

negative

gain

cell-cone

feedback

output

horizontal in cones.

Input-output

the synaptic

near

the

dark

synapse

and surround

Current

Opinion

horizontal

improves

outer

retina

the

cells and

CABA

cell

cells

and cones The sign-inverting (negative) feedback signal from HCs to cones was first recorded in the turtle retina [I], and subsequently in perch (21, carp [3,4], and tiger

In

which

feedback

with the highest The

horizontal

of the photoreceptor

range and mediates

in second-order

in Neurobiology

The primary neural control apparatus for the photoreceptor synapses is the negative feedback synapse between horizontal cells (HCs), the second-order retinal neurons with broad receptive fields, and cone photoreceptors. As I will discuss in this review, this feedback synapse improves the reliability and stability of the photoreceptor outputs. It also constitutes a neural pathway, which can be used to adjust the dynamic range and mediate color opponency and surround responses in second-order retinal neurons. In addition to the HC-cone feedback synapse, recent evidence has suggested that feedback controls may exist in the outer retina in a self-regulatory fashion: photoreceptors and HCs releasing substances that modulate their own synaptic outputs.

potential.

the reliability

of the

is the

cones.

in darkness,

relations

the dynamic

responses

The vision process begins with the photoreceptors. They convert light into an electrical signal which is subsequently sent to higher centers in the brain. As photoreceptors represent the origin of light-evoked responses, they dictate information processing for the entire visual system. It is of great importance for the visual system to provide neural controls which can ensure photoreceptor outputs and allow enough adjustability for the photoreceptor synapses to perform their complex tinctions.

horizontal

USA

gain is light-dependent

Introduction

synapse between

in

Texas,

horizontal

cells release

synapses. It also modulates

opponency

Feedback

Houston,

retinal

color

neurons.

1992, 2:462-468

salamander [ 5-7,8**]. Light hyperpolarizes the HCs and their response feeds back to cones through the sign-inverting synapse, resulting in a depolarizing response in the cones. Under normal conditions it is quite difficult to observe a clear feedback response in cones, because the depolarizing feedback response is often masked by the hyperpolarizing light-evoked response. In order to overcome this difficulty five methods have been employed to elicit feedback responses in cones: first, delivering an annulus of light while a center light spot is applied to desensitize the impaled cone [l-5,7,9] ; second, injecting current pulses into the HCs [l] ; third, injecting current pulses into rods that polarize the HCs [6] ; fourth, applying a HC neurotransmitter or its analogues to cones [3,4,10,11]; and fifth, truncating the cone outer segment so that the masking effect of the photocurrent can be removed [8**]. Each of these methods has its advantages and disadvantages [WI, but a consistent description of the detailed mechanisms of the HC-cone feedback synapse has emerged from these studies. In darkness, HCs are depolarized by the continuous flow of photoreceptor neurotransmitter (glutamate), which results in a high rate of HC neurotransmitter release. In many lower vertebrates, the primary HC neurotransmitter is y-arninobutyric acid (GABA) [ 12-161. GABA, released from HCs in darkness, opens Cl- channels in cones, possibly through GABA* receptors [8**,10,11,15]. The reversal potential of the GABA,-mediated Cl- conductances is estimated to be below - 50 mV in turtle cones [9,10], and around - 65 mV in tiger salamander cones [ 80~1. As the resting potential of cones is between - 30mV and - 40mV [ 10,11,16,171, GABA released from HCs hyperpolarizes the cones tonically in darkness. In the

Abbreviations L-APLL-a-amino+phosphonobutyrate; B-cone-blue-sensitive cone; CSARF-center-surround antagonistic receptive field; DBC-depolarizing bipolar cell; GABA--y-aminobutyric acid; C-cone-green-sensitive cone; I-K-horizontal cell; R-cone-red-sensitive cone. 462

@ Current

Biology

Ltd ISSN 0959-4388

Feedback connections

and operation

(b)

-60

of the outer

-40

-50

plexiform

layer of the retina Wu

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V cone (mV)

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3 Time(s)

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-60

-50

-40

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-20 V,, (mV)

Fig.1. (a) (9 Voltage responses

of a truncated cone to a light step in the presence of hyperpolarizing current of various intensities (Icone,right margin) passed into the cone through the recording electrode. (ii) A simultaneously recorded horizontal cell (HC) response. Note that the light response of the truncated cone reverses when the cell is hyperpolarized by - 0.15 nA of current. Resting potential of the truncated cone is about -40mV and that of the HC about -21 mV. (b) Input-output relations of the HC-cone feedback synapse. Voltage ordinate) of the simultaneously recorded HC and truncated cone at the cone resting potential (- 40 mV, points (Vnc:abscissa; V,,,,: top curve), and at - 52.5 mV (with - 0.05 nA current), - 65 mV (with - 0.10 nA current), and - 75 mV (with - 0.15 nA current). Solid triangles represent a similar plot of another pair of HC (resting potential, - 21.5 mV) and truncated cone (resting potential, - 44.5 mV). (c) Input-output relation of the HC-cone feedback synapse for light-evoked responses. The curve is bell-shaped with negative slope gains (varied from -0.33 to 0) where Vnc is between - 20 mV and - 52 mV, and positive slope gains (varied from 0 to + 0.8) where V,, is between - 52 mV and - 72 mV. Slope gains were obtained by measuring the slopes of the curve at various V,,. Chord gains (measured from the origin to various points on the curve) are always negative. Data from [8**1.

presence of light stimuli, HCs are hyperpolarized, and thus GABA release is suppressed. This results in the closure of Cl- channels and a membrane depolarization in cones [ES-,161. Because of synaptic delays and the relatively slow HC response rise time [ 18,19], the feedback response may sometimes be observed as a delayed depo-

larizing sag in the cone light response [8-l, The cone response sag, however, cannot be completely attributed to the feedback signal, because hyperpolarization-activated time-dependent currents in cones are at least partially responsible for the slow repolarization in the cone response [ 201.

463

464

Sensory

systems

Input-output cell-cone

relations feedback

of the horizontal

synapse

Input-output relations and voltage gains of the HC+one feedback synapse have been studied by using the truncated cone method in the tiger salamander retina [@*I. This method is advantageous over others in that graded depolarizing feedback responses can be recorded in the absence of a cone photoresponse (as cone outer segments are truncated). HCs, which were uniformly polarized by whole-field illumination, were recorded simultaneously with the truncated cone so that the pre- and postsynaptic light responses of the HC-cone feedback synapse could be simultaneously monitored. Input-output relations, defined as the ratio of the presynaptic (HC) and postsynaptic (cone) voltage changes while all presy naptic cells are uniformly polarized, were obtained. The slopes of the input-output relations at various voltages represent the voltage gain (slope gain) of the synapse. Figure la shows the feedback light responses of a truncated cone at various voltages (polarized by hyperpolar izing currents) and the simultaneously recorded HC response. The feedback light response in the truncated cone becomes smaller as the cone is hyperpolarized, and reverses at about - 67 mV. The input-output relations at various cone potentials, obtained by plotting the simultaneous voltage points of the HC and truncated cone responses, are given in Fig.lb. At any given cone voltage, the highest slope gain (a negative value) is near the HC resting potential (VHc = - 20 mV), and the slope gain decreases as the HC becomes hyperpolarized. As the cone is hyperpolarized from its resting potential (V,,,, = - 40 mV), the slope gain decreases because the feedback response approaches its reversal potential. The negative slope gain becomes a positive slope gain when the cone is polarized below - 67 mV, the reversal potential of the feedback synapse. Based on these observations, one can conclude that the light-evoked feedback response in intact cones (outer segments attached) is controlled by two factors: first, the magnitude of the postsynaptic conductance decrease (due to the reduction of HC neurotransmitter) increases as brighter light gives rise to a larger HC hyperpolarization; and second, the driving force (V,,, -ES) of the postsynaptic current decreases as brighter light results in hyperpolarization of the cone, bringing it closer to the reversal potential of the feedback synapse. These two factors exert opposite effects on the feedback light responses in cones and thus result in a bell-shaped inputoutput relation (Fig.lc; for detailed procedures for obtaining this relation, see [So*]>. The slope gain of the feedback synapse for light-evoked signals is negative at low light intensities (small HC responses) and positive at high light intensities (large HC responses). The maximum feedback response in cones (when the chord gain, measured from the origin to various points on the curve, is of the highest absolute value) is observed when VHc = - 52 mV (slope gain is zero). An important implication of the bell-shaped input-output relation for light-evoked feedback signals (see Fig.lc) is that the strength of the feedback signal in a given cone decreases with the intensity of light falling directly onto it,

but increases with that falling onto other photoreceptors. This spatial discrimination of light enhances spatial contrast in the retina; the antagonistic response of a cone (and thus bipolar cells and ganglion cells) is greatest when the cone itself is not directly stimulated by light. When cones are directly stimulated by light the antagonistic response decreases and eventually disappears as the direct light hyperpolarizes the cone to the feedback reversal potential [7].

Functions

of the horizontal

cell-cone

feedback

synapse in the outer retina Horizontal

cell-cone

performance

feedback

synapse

of the photoreceptor

improves

output

the

synapses

The HGcone feedback synapse constitutes a negative feedback circuit for the photoreceptor output synapses. Based on the principles of system analysis, negative feedback loops improve the reliability, signal-to-noise ratio, response band width, and stability of the forward signals [21]. In the retina, the photoreceptor-bipolar-ganglion cell synapses constitute the direct and express route for signal transmission between the photoreceptor and the brain. The HCxone feedback synapse helps to improve the performance and accuracy of signal transfer in this pathway.

Horizontal dynamic

cell-cone

feedback

ranges of retinal

synapse

bipolar

modulates

cells

In the vertebrate retina, different types of neurons operate within different light intensity (dynamic) ranges. The dynamic ranges for photoreceptors and horizontal cells, for example, are much wider than those of the bipolar and ganglion cells [22-241. As photoreceptorbipolar synaptic transmission is limited within a window of the photoreceptor voltage [23,24], a tonic negative feedback signal can shift the dynamic range of bipolar cells towards the right in the intensity axis (Fig.2). Physiologically, when a steady background illumination tonically activates the feedback synapses between HCs and cones, the operating range of the bipolar cells shifts to the right so that a brighter light stimulus is required to generate a given bipolar cell response. This synaptic arrangement enhances the simultaneous contrast of the visual system: the brighter the background (ambient) light, the brighter the stimulus is required to generate a given response. Bipolar cells are good contrast detectors because their narrow dynamic ranges allow steep V-log I relations (larger voltage changes per unit change in light intensity). As the feedback synapse can shift the dynamic ranges along the intensity axis, the bipolar cell operation can still cover a wide intensity range while background lights of various intensities are applied to the retina.

Horizontal opponency

cell-cone in retinal

feedback

synapse

mediates

color

neurons

In humans and many vertebrates that exhibit rich color vision, there are three spectrally distinct types of cone photoreceptors: the red-, green-, and blue-sensitive cones

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(V-log I) curves for (9 a cone and (ii) a bipolar cell are plotted as solid lines when no background illumination is present. The two horizontal lines in the upper plot indicate the voltage window for cone-to-bipolar cell synaptic transmission. Broken curves represent the V-log I plots for the cone and bipolar cell in the presence of background illumination. The amplitude of cone responses is reduced by sign-inverting feedback signals from the horizontal cells. The V-log I curve of the bipolar cell is shifted to the right. V,,,, and Vbipolar are nor1 malized cone and bipolar voltage responses. The arrows indicate the transition from darkness to bright background illumination. Data from 1241.

[25,26]. It is a common misconception that cones can distinguish colors. This is not true because although cones have different sensitivities to lights of different

(a)

and operation

of the outer

plexiform

layer

of the retina

465

Wu

color, they cannot distinguish between them. Take the red-sensitive cone (R-cone) as an example. If one delivers a red light of a certain intensity and a green light of a higher intensity (so that the cone pigment has equal probability of absorbing the two Lights), the R-cone will give identical responses, a phenomenon referred to as the principle of univariance [27]. Color encoding in the visual system begins at second-order retinal neurons, which exhibit color opponency: light of certain wavelengths elicits depolarizing responses, whereas light of other wavelengths elicits hyperpolarizing responses. These cells can truly distinguish between colors because no matter how one adjusts the Light intensity, light of different colors elicits responses of different polarities. The best-studied color-opponent secondorder retinal cells are the fish horizontal cells, and their color opponency is mediated by the feedback synapses between HCs and cones. Figure 3a shows the anatomical connections between the three spectral classes of cones and the three types of HCs (Hl,H2,H3) in the goldfish retina [26]. The Hl HC (L-type) receives signpreserving synaptic inputs primarily from R-cones, and has feedback via sign-inverting synapses to all three types of cones: R-cones, green-sensitive cones (G-cones), and blue-sensitive cones (B-cones). H2 (biphasic C-type) receives sign-preserving inputs from G-cones, which consist of responses derived from the G-cone photocurrent, and from Hl through the feedback synapse. This synaptic arrangement results in hyperpolarizing responses to short-wavelength stimuli and depolarizing responses to long-wavelength stimuli in H2. H3 (triphasic C-type) receives sign-preserving input from B-cones, which consist of responses derived from B-cone photocurrent, and from Hl and H2 through feedback synapses. This arrangement gives rise to hyperpolarizing responses to long-and short- wavelength stimuli, and depolarizing re-

0J) Hl

H2

Fig.3. (a) Horizontal in the goldfish and

cellLcone

retina.

C, green-sensitive

sic (C-type) zontal

and triphasic

K-type)

ows represent

sign-preserving

whereas

white

arrows

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feedback

age

responses of

(42&720

nm)

responses diction foot

light

HI,

hori-

synapses, sign-in-

[261. (b) Voltand

H3

to

wavelengths

polarity

of the

agrees very well with the pre-

of the model

(AV

H2,

of various 1241. The

H2,

Solid arr-

represent

synapses of

HI,

(L-type), bipha-

cells (HCs), respectively.

steps

R, red-,

cones.

and H3 are monophasic H3

synapses

B, blue-,

in Fig.3a).

of Stell and Light-

466

Sensory _.

systems

sponses to medium-wavelength stimuli in H3 [3,4,28]. Figure 3b shows the voltage responses of Hl, H2 and H3 to fight steps of various wavelengths. The color opponency of other second-order cells, such as red-green bipolar cells, is also mediated at least partially by the feedback synapses between HCs and cones [ 291. Horizontal surround

cell-cone responses

feedback synapse in retinal

bipolar

mediates cells

Center-surround antagonistic receptive field (CSARF) organization is the basic means for encoding spatial inforRetinal bipomation in the visual system [30,31,32*,33]. lar cells are the first neurons along the visual pathway that exhibit CSARF. The center inputs of bipolar cells are mediated by photoreceptor-bipolar cell synapses and the surround inputs are mediated by HCs, and perhaps amacrine cells [30,31,32*]. In the outer retina, the HC-mediated surround input is carried by two synaptic pathways: the HC-cone-bipolar

cell feedback pathway (synapses 1 and 2 in Fig.4A) and the HC-bipolar cell feedforward pathway (synapse 3 in Fig.4A). Figure 4B shows the input-output relations of the HCconedepolarizing bipolar cell (DBC) feedback synaptic pathway (solid curve in the lower left quadrant). This relation is obtained by combining the input-output relation of the HCcone feedback synapse at the cone dark potential (V,.,,, = - 40 mV, upper-left quadrant and top curve in Fig.lb) and the input-output relation of the coneDBC synapse (obtained by simultaneous recordings from cones and DBCs while rod responses are suppressed; SM Wu, unpublished data). The voltage span (VDBc) of the resultant input-output relation (H&cone-DBC feedback synaptic pathway) is about three times larger than that of the HC-DBC feedforward synapse (dashed curve in the lower left quadrant, obtained by blocking the feedback pathway with L-a-amino-4-phosphonobutyrate (I.-AP4) [32*]). These results suggest that although both feedback and feed-

I3

A S

Fig.4. (Ai Summary

C

S

diagram of the major synaptic connections of the on- or depolarizing bipolar cell (DBC) pathway. Voltage responses to center (C) and surround (9 light stimuli are shown in each cell. R, rod. C, cone. H, horizontal cell. A, amacrine cell. C,,, on-ganglion cell. (+I, sign-preserving chemical synapse. (-), sign-inverting chemical synapse. Synapse 1 is the HC-cone feedback synapse, synapse 2 is the coneDBC synapse, and synapse 3 is the HC-DBC feedforward synapse. (B) Input-output relation of the HC-DBC feedback synaptic pathway (solid curves) and the feedforward synapse (synapse 3; dashed curve in lower left quadrant). The upper left quadrant shows the input-output relation of the HC-cone feedback synapse (synapse I) obtained with the truncated cone preparation (top curve in Fig.lb). The lower right quadrant shows the input-output relation of the cone_DBC synapse (synapse 2; SM Wu, unpublished data). Data pornts in the lower left quadrant were obtained by projecting data points In the HC-cone feedback input-output relation to the upper-right,, lower-right and then lower-left quadrants (broken arrows). This procedure gives rise to the input-output relation of the HC ~DBC signals through the feedback pathway (solid curve in lower left quadrant). The voltage gain of the HC-DBC feedback pathway equals the product of the HC-cone feedback synapse and that of the cone-DBC synapse. Near the HC dark potential (-20mV), for example, the voltage gain of the HC-DBC feedback pathway = (voltage gain of the HC-cone feedback synapse) x (voltage gain of the coneDBC synapse) = C-0.33) x (- 1.75) = +0.58. The dashed curve in the lower left quadrant was obtained by recording the HC and DBC responses in the presence of 2OpM L-AP4, whrch selectively blocks the photoreceptor-DBC synapses without affecting the HC responses 132.1. Therefore the dashed curve represents the Input-output relation of the HC-DBC feedforward synapse, because one of the synapses (the coneDBC synapse, 2 rn Fig.4A) in the feedback pathway IS blocked by L-AP4.

Feedback

connections

forward synapses are functional, the feedback synaptic pathway is predominantly responsible for mediating the surround responses of bipolar cells.

Other

forms of feedback

control

in the outer

retina Most of this review has focused on the HCTone feedback synapse, the primary feedback control apparatus in the outer retina. This synapse exhibits many of the basic properties of conventional chemical synapses. GABA, a classical inhibitory neurotransmitter, is used by the presy naptic cells (HCs) in many species, and is released upon membrane depolarization. GABA opens Cl- channels in postsynaptic cells (cones) and inhibits the light-evoked responses. In addition to the H&cone feedback synapse, recent evidence has suggested that there are several nonconventional feedback control loci in the outer retina. It has been shown that glutamate, the neurotransmitter released from photoreceptors, opens Cl- channels in tiger salamander cones [34], and results in inward currents in both rods and cones in turtles [35]. These results suggest that the photoreceptor neurotransmitter self-regulates (auto-feedback) its own release by controlling the presynaptic membrane voltage. In addition, a releasable vesicular pool of Zn2+ ions has been localized in rods and cones in the tiger salamander retina, and application of micromolar Zn2 + suppresses glutamate release from photoreceptors to HCs (X Qiao et al: ARGO Abstracts 1992, 331409). Zn2+ is probably co-released with glutamate from photoreceptors in darkness, and feeds back and self-regulates rods and cones to minimize the depletion of tonically released glutamate. In addition to photoreceptors, auto-feedback control also exists in HCs. In the tiger salamander retina, GABA released from HCs self-regulates the HC response rise time [19], perhaps by opening Cl- conductances in the HC membrane (M Kamermans and FS Werblin: ARGO Ab s&acts 1991, 32:1190). This auto-feedback system may be used to adjust the response time courses and the frequency responses of the input and output synapses of retinal HCs [l&19].

and operation

plexiform

layer

of the retina

Wu

has been obtained from lower vertebrates, indirect measurements from HCs indicate that feedback to cones may also exist in mammalian retinas [ 37,381. Moreover, negative neural feedback is probably a general control strategy used by the entire visual system to process visual information. In the inner retina, for example, amacrine cells (third-order neurons) make negative feedback synapses on bipolar cell (second-order neurons) synaptic terminals [ I3,30,39]. In the visual cortex, feedback connections have also been observed [40]. Facts that have been learned from the HCcone feedback synapse in the outer retina not only tell us how information is processed in the first visual synapses, but also shed considerable light on our understanding of the rest of the visual system.

Acknowledgements This work was supported by grants from National Institutes of Health (EYO4446), the Retina Research Foundation (Houston), Research to Prevent Blindness, Inc., and Human Frontier Science Program.

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Wn SM: Input-Output Relations of the Feedback Synapse Between Horizontal Cells and Cones in the Tiger SaIamander Retina. J Neurop@siol 1991, 65:1197-1206. ^. This paper provides perhaps the most comprehensive study ot the input-output relations of the HCxone feedback synapse. The presynaptic (HCs) and postsynaptic (cones) cells were recorded from simultaneously while whole-field illumination was used to uniformly polarize the HC network. The cone outer segment was truncated to avoid a masking effect of photocurrent on the feedback signal Detailed mechanisms of the input~output relations and voltage gains (slope gain and chord gain) of the feedback synapse are described. 9.

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YANG XL, WI] SM: Modulation of Rod-Cone Light. Science 1989, 244:352-354.

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YANG XL, Wu SM: Effects of Background Illumination on Horizontal Cell Responses in Tiger Salamander Retina. J Neurosci 1989, 9:815-826.

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YANG XL, Wu SM: Effects of Prolonged Light Exposure, Gamma-Aminobutyric Acid and Glycine on the HC Responses in the Tiger Salamander Retina. J Neuropbysiol1989, 244352-354.

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A: Physiological and Morphological Identification of Horizontal, Bipolar, and Amacrine Cells in the Goldfish Retina. J Physiol 1970, 207:623433. KANEKO

YANG XL, Wu SM: Feedforward Lateral Inhibition: Input-Output Relation of the Horizontal Cell to Bipolar Cell Synapse in the Tiger Salamander Retina. Proc Nat1 Acad Sci USA 1991, B&331&3313. This paper provides evidence for the feedforward synaptic pathway beg tween HCs and DBCs. Addition of 20 PM L-AP4 selectively blocks the photoreceptor-DBC synapse without affecting the HCs. An input-output relation of the HC-DBC feedforward synapse was obtained. In comparison with the HC-cone-DBC feedback pathway, the feedforward synapse only contributed one quarter to one third of the total surround response in DBCs. 32. .

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H~I~ELDH, WIESELTN: Receptive tion and Functional Architecture J Pkysiol 1962, 16O:lOGl54.

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SARAN~SM, EVERETT K, ATTWXL D: A Presynaptic Action of Glutamate at the Cone Output Synapse. Nature 1988, 332:451-453.

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HEIDELRERGERR, MA~EWS G: Inhibition of Calcium Influx and Calcium Current by y-Aminobutyric Acid in Single Synaptic Terminals. Proc Nat1 Acad Sci USA 1991, 88:7135-7139. This paper provides the first evidence that GABA may modulate presynaptic Ca*+ currents in retinal neurons. GABA released from amacrine cells suppresses the Ca*+ current in their presynaptic cells (bipolar 36. .

cells). This type of feedback nals in the outer retina.

37.

control

may exist in photoreceptor

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