Response Sensitivity and Voltage Gain of the Rod- and Cone-Bipolar Cell Synapses in Dark-Adapted Tiger Salamander Retina
Xiong-Li Yang and
Samuel M. Wu
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas 77030
 |
ABSTRACT |
Yang, Xiong-Li and Samuel M. Wu. Response sensitivity and voltage gain of the rod- and cone-bipolar cell synapses in dark-adapted tiger salamander retina. J. Neurophysiol. 78: 2662-2673, 1997. Rods, cones, and bipolar cells were recorded in superfused, flat-mounted isolated retinas of the larval tiger salamander, Ambystoma tigrinum, under dark-adapted conditions. Voltage responses of 24 rods, 15 cones, and 41 bipolar cells in dark-adapted retinas to 500 nm light steps of various intensities were listed and fitted with hyperbolic functions, and their step sensitivities and relative sensitivities (log
) were estimated. In the linear response-intensity ranges, the step sensitivity of rods, SS(rod), is
1.0 mV photon
1 µm2 s or 0.034 mV Rh*
1 s rod and that of the cones, SS(cone), is ~0.00146 mV photon
1 µm2 s or 0.000048 mV Rh*
1 s rod. The rod and cone responses were relatively homogenous with little variations in response amplitude and sensitivity. In contrast, bipolar cell responses were heterogenous with large variations in response amplitude and sensitivity. The maximum response amplitude of bipolar cells varied from 5 to 25 mV, and the relative response sensitivity (log
) varied >6 log units (
8.11 to
2.32). The step sensitivity of bipolar cells in the linear response-intensity range varied from 0.0000438 to 51.82 mV photon
1 µm2 s. Bipolar cells in dark-adapted tiger salamander retinas fell into two groups according to their relative sensitivities with very few cells falling in the intermediate light intensity region. The mixed bipolar cells (DBCM and HBCM) exhibited relative response sensitivity ranged from
8.11 to
5.54, and step sensitivity ranged from 1.22 to 51.82 mV photon
1 µm2 s. The cone-driven bipolar cells (DBCC and HBCC) exhibited relative response sensitivity ranged from
3.45 to
2.32, and step sensitivity ranged from 0.0000438 to 0.00201 mV photon-1 µm2 sec. The chord voltage gain of the rod-DBCM or rod-HBCM synapses near the rod dark membrane potential ranged from 1.14 to 48.43 and that of the cone-DBCC or cone-HBCC synaptic gain near the cone dark membrane potential ranged from 0.03 to 1.38. The highest voltage gains were found near the rod or cone dark membrane potentials. By the use of linear subtraction method, we studied the synaptic inputs from cones to five mixed bipolar cells, and the voltage gains of the cone synapses in each of the bipolar cells were very close to the voltage gain of the rod synapses. This result suggests that although the responses of mixed bipolar cells are mediated mainly by rods when lights of short and medium wavelengths are used, their responses to long wavelength lights (>650 nm) are mediated by both rods and cones with comparable synaptic gains. Functional roles of the mixed and cone-driven bipolar cells in information processing in dark-adapted retinas are discussed.
 |
INTRODUCTION |
In the vertebrate retina, rod photoreceptors are responsible for detecting dim light signals under dark-adapted conditions whereas cone photoreceptors detect bright signals under dark- and light-adapted conditions (Dowling 1987
; Schultze 1866
). Rod and cone signals are transmitted to retinal bipolar cells that relay visual information to retinal ganglion cells and subsequently to the brain (Dowling 1987
; Wu 1994
). There are two ways that rods and cones converge signals to bipolar cells: they either send inputs to separate populations of bipolar cells (e.g., mammals) or to mixed bipolar cells (e.g., fish) (Boycott and Kolb 1973
; Kaneko 1973
; Kolb 1970
; Kolb and Famiglietti 1974
; Schwartz 1974
; Stell 1967
). In amphibians, bipolar cells are considered as mixed (Lasansky 1973
, 1978
; Werblin and Dowling 1969
), but recent evidence in dark-adapted tiger salamander retinae has suggested that bipolar cells can be divided into two groups, with one exhibiting high (rodlike) sensitivity and the other exhibiting low (conelike) sensitivity (Hensley et al. 1993
; Yang and Wu 1993
). It is not certain, however, whether these two groups of bipolar cells receive separate or mixed rod/cone synaptic inputs. Additionally, it appears that within each group, especially that of the high sensitivity, light sensitivity of individual cells varies considerably. The degree of such variation and the relationship between the sensitivity variation and synaptic gain are yet to be determined.
In this study, we systematically examined the response sensitivity and spectral properties of bipolar cells in dark-adapted tiger salamander retinae. We studied the voltage gain of the rod output synapses made on the high sensitivity bipolar cells and the relationship between rod synaptic gain and the bipolar cell light sensitivity. We also examined the synaptic inputs from cones to high-sensitivity and low-sensitivity bipolar cells. The voltage gains of the cone output synapses were determined.
 |
METHODS |
Preparation
Flat-mounted, isolated retinas of the larval tiger salamanders (Ambystoma tigrinum) purchased from Charles E. Sullivan (Nashville, TN) and KON's Scientific Company (Germantown, WI) were used in this study. Before an experiment, the animal was dark-adapted for
2 h and then decapitated under infrared illumination. The eyes were enucleated and hemisected. A piece of the posterior half of the eyecup was inverted over a hole in a piece of Millipore filter (HAO; pore size, 0.45 µm) secured in the superfusion chamber. The sclera and the pigment epithelium were removed from the retina. The entire procedure was done under infrared illumination with a dual-unit Fine-R-Scope (FJW Industry, Mount Prospect, IL). Oxygenated Ringer solution was introduced to the superfusion chamber at a rate of ~5 ml/min, so that the retina was immersed totally under solution. The control Ringer contains (in mM) 108 NaCl, 2.5 KCl, 1.2 MgCl2, 2 CaCl2, and 5 mM N-2-hydroxyethylpiperazine-N
-2-ethanesulfonic acid (adjusted at pH 7.7). The retina (photoreceptor-side up) was viewed with a Zeiss ×32 objective lens modified for the Hoffman modulation contrast optics (Hoffman Modulation Optics, Greenvale, NY). During the experiment, retinal cells as well as the electrode were observed clearly on the screen of a TV monitor connected to the infrared image converter (model 4415; COHU, Palo Alto, CA) attached to the microscope.
Recording
Intracellular recordings were made from photoreceptors and bipolar cells with micropipettes drawn with a modified Livingston puller with Omega Dot tubing (1.0 mm OD and 0.5 mm ID). The micropipettes were filled with 2 M potassium acetate and had tip resistances measured in Ringer solution of 100-600 M
. The electrodes were positioned under visual control with infrared illumination. The impalement was facilitated by adjusting the negative capacitance in the electrode headstage. Voltage traces were monitored with an oscilloscope (model 5500A; Tektronix, Beaverton, OR) and stored on magnetic tapes (Model 820, Vetter, Rebersberg, PA).
Light source
The preparation was stimulated with a dual-beam photostimulator. Two independent light beams, the intensity and wavelength of which could be adjusted by neutral-density filters and interference filters, were provided by quartz halogen sources. The light was transmitted to the preparation by way of the epi-illuminator and the objective lens of the microscope. The spot diameter on the retina could be adjusted by a diaphragm in the epi-illuminator. In most experiments described, small spot illumination (400-600 µm in diameter) covering the receptive field center (Borges and Wilson 1987
, 1990
) was used. The intensity of light sources was measured with a radiometric detector (United Detector Technology, Santa Monica, CA). The intensity of unattenuated 500 nm light(log I = 0) is 2.05 × 107 photons µm
2 s
1. A typical tiger salamander rod outer segment is 25 µm long and 10 µm in diameter (Diamond and Copenhagen 1995
). Taking a specific axial density of rhodopsin of 0.015 µm
1 and quantum efficiency for photoisomerization of 0.67 (Dartnall 1968
; Liebman and Entine 1964
), the photoisomerization cross section (PIC) can be calculated by the following equation
|
(1)
|
Thus 1 photon µm
2 s
1 is approximately equivalent to 30 Rh* (activated rhodopsin molecules) rod
1 s
1.1
Light response analysis
Voltage responses of rods, cones, and bipolar cells were digitized and analyzed (signal average and response subtraction) with a computer A-D system (BIOPAC Systems, Santa Barbara, CA, Model MP100A). When the peak voltage responses were plotted against light stimulus intensity, data points were fitted by the following equation (Thibos and Werblin 1978
)
|
(2)
|
where V is the response amplitude, Vmax is the maximum response amplitude,
is the light intensity that elicits a half-maximal response, N is a constant, tanh is the hyperbolic tangent function, and log is the logarithmic function of base 10. In this article, we used the V-log I plot for our analysis (the right-hand term of Eq. 2) and for such plots the light intensity span (range of intensity that elicits responses between 0.05 and 0.95% of Vmax) of a cell equals to 2.56/N (Thibos and Werblin 1978
).
 |
RESULTS |
Light responses of rods, cones, mixed, and cone-driven bipolar cells under dark-adapted conditions
We first studied the response sensitivities of various dark-adapted retinal cells. In Table 1A, we list the response amplitudes of 24 rods, in Table 1B, the responses of 15 cones, and in Table 2, the responses of 41 bipolar cells to 500-nm 0.5-s light steps recorded under dark-adapted conditions. Data points of each cell were fitted by Eq. 2 given in METHODS, and the relative sensitivity, defined as the intensity of light eliciting half-maximal responses (log
), and the Hill coefficients (N) are listed in Tables 1 and 2. Because the rod responses to
8.3 and
7.67 light steps and the cone responses to
5.3 light steps were so small (also see Fig. 1), each value in Table 1 marked with an asterisk was obtained by signal averaging >20 repeatedly recorded responses. The mean responses (±SD) of the 24 rods and 15 cones are given in Table 1. Additionally, we calculated and listed in Table 1 the average step sensitivity, SS, defined as the voltage response divided by the absolute light intensity, of the rods and cones in their linear response-intensity range [within which the response amplitude is proportional to the light intensity, and thus SS =
V/IS is constant (Baylor and Hodgkin 1973
; Yang and Wu 1996
)]. For rods, the linear response-intensity range for 500-nm light steps was between
8.3 and
7.3 log unit attenuations, which elicited averagevoltage responses of 0.11-1.04 mV. For cone responsesto 500-nm light steps, the linear range was between
5.3 and
4.3, which elicited average voltage responses of 0.15-1.5 mV. Therefore SS(rod) is ~1.0 mV photon
1 µm2 s or 0.034 mV Rh*
1 s rod and SS(cone) is ~0.00146 mV photon
1 µm2 s or 0.000048 mV Rh*
1 s rod. It is important to note that under dark-adapted conditions, the variations in response amplitude and sensitivity among different rods or cones were relatively small, with log
values (
5.56 ± 0.33 for rods, and
2.93 ± 0.29 for cones; means ± SD) spreading over <1 log unit of light intensity and response amplitude variations <30%. This suggests that rod and cone light responses in dark-adapted tiger salamander retinas are quite homogeneous. For this reason, we plot in Fig. 1A the mean voltage responses (with standard deviations) of the rods and cones against the light intensity (V-log I relations, the smooth curves were fitted by Eq. 2). These two V-log I relations approximately represent the light responses of the majority (if not all) rods and cones in dark-adapted tiger salamander retinas.

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| FIG. 1.
Response-intensity (V-log I) relations of 24 rods (A; , mean values; error bars are the standard deviations from Table 1A) and 15 cones ( , mean values; error bars are the standard deviations from Table 1B). B: 41 bipolar cells ( , DBCs; , HBCs from Table 2). Each set of responses were fitted by Eq. 2 in METHODS, and the N and log values are given in Tables 1 and 2. In B, the 29 cells ( ) in the left portion are named mixed bipolar cells, and the 11 cells ( ) in the right portion are named cone-driven bipolar cells. - - - (HBC41 in Table 2), middle portion, does not belong to either groups.
|
|
In contrast to rods and cones, there is considerable variation in response amplitude and light sensitivity among individual bipolar cells in dark-adapted tiger salamander retinae. As evident from the data shown in Table 2, the maximum light response amplitudes of bipolar cells varied from 5.5 to 25 mV, and the relative sensitivity (log
) in these cells spread over nearly 6 log units. Because of such response heterogeneity, each bipolar cell must be treated individually. In Fig. 1B, we plot the V-log I relations of the 41 bipolar cells listed in Table 2 and fit the responses of each cell with Eq. 2 (continuous curves). It is evident from this figure that bipolar cells, either the DBCs or the HBCs, fall into two groups, with one exhibiting high sensitivity to 500-nm light steps (Fig. 1B, left) and the other exhibiting low sensitivity to 500-nm light steps (Fig. 1B, right). Very few cells fall in the intermediate range along the intensity axis (only 1 of these cells had maximum response amplitude >5 mV, HBC41, the dotted curve in Fig. 1B). We name the high-sensitivity bipolar cells mixed bipolar cells (DBCM and HBCM). This name is more appropriate than the term "rod-dominated" used in our earlier publications (Hensley et al. 1993
; Yang and Wu 1993
) because, as we will show later in this paper, such high-sensitivity bipolar cells under certain stimulus conditions exhibit substantial cone-mediated light responses. The low-sensitivity bipolar cells are named cone-driven cells (DBCC and HBCC) because their light responses under all stimulus conditions are mediated by cones (they give no response to light stimuli dimmer than the cone response threshold).
Figure 2 shows the average (± SD) spectral sensitivity of five DBCMs, seven HBCMs, three DBCCs, and five HBCCs (
,
,
and
) in dark-adapted retinas. The spectral sensitivities of the rods and the cones are also given in solid and open circles and continuous curves. It is evident from this figure that the spectral sensitivity of the cone-driven bipolar cells (DBCC and HBCC) closely resembles that of the cones. The spectral sensitivity of the mixed bipolar cells (DBCM and HBCM) fits the spectral sensitivity of the rods very well at short wavelengths, but it is substantial higher than the rod sensitivity at long wavelengths (700 nm, Fig. 2, ). This wavelength-dependent deviation of sensitivity suggests that voltage responses of mixed bipolar cells are mediated primarily by rods when stimulated with lights of short and medium wavelengths. They receive substantial cone inputs when long wavelength lights (>650 nm) are used. Further experiments on cone inputs to mixed bipolar cells will be described in a subsequent section.

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| FIG. 2.
Normalized spectral sensitivity relations of a rod ( and  ),a cone ( and  ), the mean values of 5 DBCMs ( ), 7 HBCMs ( ), 3DBCCs ( ), and 5 HBCCs ( ). Long error bars, SD for the mixed bipolar cells; short error bars, SD for the cone-driven bipolar cells. Thick error bars are for the HBCs, and thin error bars are for DBCs. , sensitivity of mixed bipolar cells are substantially higher than that of the rod at 700 nm.
|
|
We next calculated the step sensitivity, SS, of each bipolar cell and list them in the last column of Table 2. For the mixed bipolar cells, we estimated SS from their voltage responses to the 500 nm/
8.3, 500 nm/
7.67 and 500 nm/
7.3 light steps, which lay within the linear response-intensity range of the rods. For the cone-driven bipolar cells, we estimated SS from their responses to the 500 nm/
5.3 and 500 nm/
4.3 light steps, which lay within the linear response-intensity range of the cones (examples of how SS values of bipolar cells are calculated are given in the next paragraph). It is evident in Fig. 1B that there are larger variations in response amplitude and sensitivity within the mixed bipolar cells than within the cone-driven bipolar cells. For the DBCMs and HBCMs, peak response amplitudes ranged from 5.5 to 25 mV, and log
values varied over 2.57 (low =
8.11 and high =
5.54) log units. For the DBCCs and HBCCs, peak response amplitudes ranged from 6 to 13.5 mV, and log
values covered only 1.13 (low =
3.45 and high =
2.32) log units (see also Table 2). After analyzing the first several bipolar cells, we thought that the large variations within mixed bipolar cell responses might be caused by the high susceptibility of these cells to light adaptation: cells with smaller peak amplitudes and higher log
values were recorded under more light-adapted conditions than those with larger peak amplitude and lower log
values. We then carefully kept records on the adaptational conditions of each bipolar cell recorded subsequently and found that mixed bipolar cells recorded under nearly identical adaptational conditions (in 2 cases, 2 bipolar cells were recorded simultaneously) exhibit much wider response variations than the cone-driven cells. In fact, in several instances, a mixed bipolar cell with smaller amplitude and higher log
values was recorded before (while the retina was slightly more dark-adapted) a second mixed bipolar cell with larger amplitude and lower log
value was recorded in the same retina.
To illustrate the response waveform and light sensitivity of various types of bipolar cells, we show in Fig. 3 the voltage responses of a rod, a cone, a DBCM, a HBCM, a DBCC and a HBCC to 500-nm light steps of different intensities recorded from dark-adapted tiger salamander retinas. Among the 29 mixed bipolar cells listed in Table 2, we chose cell DBC32 and HBC35, which exhibited relatively high light sensitivity, so that we could clearly characterize their rod synaptic inputs. There are several features in Fig. 2 that warrant attention. 1) The DBCM and HBCM exhibited substantially higher sensitivity to the 500-nm light steps than the rods. For the 500-nm/
8.3 light step, the rod response was so small that it was buried in the voltage noise (the amplitude of which was obtained by signal averaging as 0.11 ± 0.06 mV, see Table 1A), the voltage responses of the DBCM and HBCM, on the other hand, were ~4 and 5 mV, respectively. This light step had the intensity of about 0.1027 photons µm
2 s
1, which approximately equals to 3.1 Rh* s
1 rod
1 (see METHODS). Thus the step sensitivities were for rods SS (rod) = 1.07 mV photon
1 µm2 s, or 0.035 mV Rh*
1 rod s, and for the bipolar cells SS (DBCM32) = 4 mV/(0.1027 photons µm
2 s
1) = 38.95 mV photon
1 µm2 s, or 1.3 mV Rh*
1 rod s, and SS (HBCM35) = 5mV/(0.1027 photons µm
2 s
1) = 48.69 mV photon
1 µm2 s, or 1.6 mV Rh*
1 rod s (SS for other bipolar cells are listed in the last column of Table 2). 2) The DBCM and HBCM exhibited voltage tails after the cessation of the light steps brighter than 500 nm/
6.3. These voltage tails resemble the rod voltage tails, and thus they are mediated by the rod inputs (Attwell et al. 1987
; Belgum and Copenhagen 1988
). The tail responses of the DBCM and HBCM appeared to outlast the rod tail responses because the voltage gains of theses bipolar cells near their dark potentials are very high (see next section). 3) The DBCC and HBCC exhibited low sensitivity to the 500-nm light steps. No responses wereobserved in these cells until the light intensity was raisedto ~500 nm/
4.3, which also gave a measurable response in cones (see Table 1B). 4) The voltage noise during the DBC light responses is substantially higher than the voltage noise during the HBC light responses. This is particularly noticeable during the voltage tails. Such difference in voltage noise is consistent with the notion that postsynaptic channels in the DBCs close in darkness and open in light, and those in the HBCs operate in an opposite manner (Ashmore and Copenhagen 1980
; Ashmore and Falk 1977
).

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| FIG. 3.
Voltage responses of a rod, a cone, a DBCM (DBC32 in Table 2), a HBCM (HBC35), a DBCC (DBC40), and a HBCC (HBC10) to 0.5-s 500-nm light steps of various intensities (in log units of attenuation, marked at bottom).
|
|
Voltage gains of the rod-DBCM, rod-HBCM, cone-DBCC, and cone-HBCC synapses
We next studied the voltage gains of the rod-mixed bipolar cell and cone-cone driven bipolar cell synapses under dark-adapted conditions. Our approach was to use the averaged rod and cone light responses described in the last section (Table 1) as the presynaptic signals and individual bipolar cell responses (Table 2) as the postsynaptic signals to determine the chord voltage gains of the synapses. We chose to determine the chord voltage gain (defined as the ratio of voltage change of the postsynaptic cell over that of a presynaptic cell when all presynaptic cells are uniformly polarized) because it could be obtained directly from measurable responses, whereas the slope gain (determined by the slope of the input-output relation) critically depended on the mathematical equations used for curve fitting (Attwell 1990
; Falk 1989
). It has been shown by previous works that the input-output relations of the photoreceptor-bipolar cell synapses are approximately exponential with the highest gain near the dark potentials (Belgum and Copenhagen 1988
; Falk 1989
; Yang and Wu 1993
). We therefore estimated the maximum chord synaptic gains by using small responses that were close to the photoreceptor dark potentials. Another reason for using small responses to estimate synaptic gain is that for the rod-DBCM and rod-HBCM synapses, the 500-nm lights eliciting small rod responses are so dim that they are far below the threshold for eliciting cone responses, and thus the gain obtained this way will reflect synaptic inputs with negligible contribution from cones. In Table 3, we list the chord voltage gains of all 40 dark-adapted bipolar cells (except HBC41) described in Table 2. Two sets of gains are given. One was determined by the ratios of individual DBCMand HBCM responses to the averaged rod response tothe
8.3 (500 nm) light step or by the ratios of individual DBCC and HBCC response to the average cone response to the
5.3 (500 nm) light steps. The second set was determined by the ratios of DBCM and HBCM responses to the average rod response to the
7.3 (500 nm) light steps or by the ratios of the DBCC and HBCC responses to the average cone response to the
4.3 (500 nm) light steps. In the first set, the
8.3 and
5.3 light steps hyperpolarized rods and cones, respectively, by ~0.1 mV below their dark potentials; and in the second set, the
7.3 and
4.3 light steps hyperpolarized rods and cones, respectively, by ~1 mV below their dark potentials. Each gain value calculated this way has a minimum range of error equals to the bipolar cell response used divided by the standard deviation of the photoreceptor response (given in Table 1). The first set of voltage gains is about three to four times higher than the second set, which is consistent with the notion that the highest gain is near the photoreceptor dark potentials. In Fig. 4, we plot the two sets of voltage gains (in log scale) of the 40 rod- and cone-bipolar cell synapses against the half-maximal intensity, log
, of each bipolar cell. Figure 4A illustrates the first set, and Fig. 4B illustrates the second set with filled circles representing voltage gains of the rod-DBCM and rod-HBCM synapses and open circles representing voltage gains of the cone-DBCC and cone-HBCC synapses. Several features in Fig. 4 warrant attention. 1) In Fig. 4, both A and B, the rod output synapses had higher voltage gains than the cone output synapses. In Fig. 4A, for example, the rod output synaptic gain ranged from 1.14 to 48.43 whereas the cone synaptic gain ranged from 0.03 to 1.38. 2) In Fig. 4, both A and B, the voltage gains appeared to be proportional to the bipolar sensitivity (defined as
log
): bipolar cells of higher sensitivity (with more negative log
values) had higher synaptic gains from their photoreceptor inputs. The proportional constant,
, determined by linear regression of each set of data points in Fig. 4 (dashed lines), gives an approximate measure of how voltage gains of photoreceptor-bipolar cell synapses vary with light sensitivity of the postsynaptic bipolar cells in dark-adapted retinas. Therefore log(gain)=
log
, or gain =
. In Fig. 4A,
(rod-BC) =
0.56/log unit of light and
(cone-BC) =
0.90/log unit of light. In Fig. 4B,
(rod-BC) =
0.49/log unit of light and
(cone-BC) =
0.93/log unit of light.

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| FIG. 4.
Plots of the 2 sets of chord voltage gains (in log scale) of the 40 rod- and cone-bipolar cell synapses against the half-maximal intensity, log , of each bipolar cell listed in Table 3. A: illustration of gain 1. B: illustration of gain 2. Filled circle, voltage gains of the rod-DBCM and rod-HBCM synapses; open circle, voltage gains of the cone-DBCC and cone-HBCC synapses. Four dashed lines were obtained by linear regression of the 4 sets of data points.
|
|
Voltage gain of the cone-HBCM and cone-DBCM synapses
For the cone-HBCM and cone-DBCM synapses in dark-adapted retinas, it is impossible to use the method described in the last section to determine voltage gain because no light stimuli selectively evoke cone responses without stimulating rods. We therefore adopted the spectral subtraction method. This method takes advantage of the difference in spectral sensitivity of the rods and cones and the linear bipolar cell voltage summation near the dark membrane potential (which will be verified later). In the tiger salamander, there is primarily only one type of rod (except for a small number of short wavelength rods) with peak sensitivity ~520 nm and one type of cones with peak sensitivity near 620 nm (Yang and Wu 1989
, 1996
). The rod sensitivity drops steeply as the wavelength increases. The sensitivity of rods to 750 nm light is ~4.8 log units lower than that to 500 nm light (Yang and Wu 1996
), and thus light stimuli 500 nm/
7.67 and 750 nm/
2.87 generated rod responses of the same amplitude, and stimuli 500 nm/
7.30 and 750 nm/
2.50 generated rod responses of the same amplitude. Because the two 500 nm lights were far below the operation range of the cone, they only elicited rod responses and therefore evoked pure rod inputs in the DBCMs and HBCMs. The two 750 nm lights elicited both rod and cone responses, and thus they evoked mixed inputs in DBCMs and HBCMs. Therefore it was possible to estimate the cone inputs in DBCMs and HBCMs by subtracting the DBCM or HBCM response to 500 nm/
7.67 light from that to 750 nm/
2.87 light. The reason for this is that the two light stimuli elicited rod responses of the same amplitude and thus the same rod-mediated postsynaptic responses in the DBCMs and HBCMs. Subtracting the rod-mediated DBCM and HBCM responses from the mixed DBCM and HBCM responses gave the cone-mediated DBCM and HBCM responses.
One basic requirement for such voltage subtraction is that the rod and cone synaptic inputs must add linearly in DBCMs and HBCMs within the voltage range of subtraction. In Fig. 5, we show that rod and cone inputs add linearly within at least the first 15-20 mV below the HBCM (cell HBC29 in Table 2) dark membrane potential. We used a 0.5-s 500 nm/
7.67 light step and a 0.5-s 750 nm/
3.3 light step tostimulate the HBCM. As illustrated in Fig. 1A, the 500nm/
7.67 light was far below the operation range of cones, thus it only stimulated rods, and therefore the HBCM response was mediated by rod input alone. The HBCM response to 750 nm/
3.3 light stimulated both rods and cones (Yang and Wu 1996
). The HBCM response to the combined beams of 500 nm/
7.67 and 750 nm/
3.3 lights is shown as the thick trace in Fig. 5. We added the HBCM response to the 500 nm/
7.67 light and that to the 750 nm/
3.3 light by a computer and showed it as the thin trace in Fig. 5. It is evident from this figure that the HBCM responses to the combined beams exhibit nearly identical amplitudes and waveform as the computer-assisted addition of the two separate responses. We repeated this addition test on one other HBCM and one DBCM in dark-adapted retinas, and they showed similar linear additive properties for rod and cone inputs. Based on these results, we concluded that the summation of bipolar cell responses was approximately linear and the subtraction analysis for studying the cone-bipolar cell synapses was a reasonable approach.

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| FIG. 5.
Demonstration of linear summation of light responses in a bipolar cell (HBCM29 in Table 2) dark membrane potential. The HBCM response to the combined beams of 500 nm/ 7.67 and 750 nm/ 3.3 lights is shown as the thick trace. Computer-assisted addition of the HBCM response to the 500 nm/ 7.67 light and that to the 750 nm/ 3.3 light is shown as the thin trace. It is evident from this figure that the HBCM responses to the combined beams exhibit nearly identical amplitudes and waveform as the computer-assisted addition of the 2 separate responses.
|
|
Figure 6 shows an example of such subtraction. Voltage responses of a rod, a cone and a HBCM (cell HBC29 in Table 2) to 0.5-s 750 nm/
2.87 and 500 nm/
7.67 light steps are given in the left and middle columns. The difference responses of these two columns (obtained by computer subtraction, see METHODS) are given in the right column (750 nm/
2.87 to 500 nm/
7.67). It is worth noticing that in this figure, the rod responses to the two light stimuli are of virtually identical amplitude and waveform. This gives zero difference responses for the rod (right column, top), and thus the difference response for the HBCM is mediated completely by the cones. The ratios of the HBCM difference response to the cone response gave rise to the chord gain of the cone-HBCR synapse under dark-adapted conditions. For the HBCM in Fig. 6, the voltage gain was ~13.5. By using this method, we analyzed two other HBCMs and two DBCMs in dark-adapted tiger salamander retina. The chord voltage gain for the cone input synapses in bipolar cell HBC35 is 17.2, in HBC03 is 11.7, in DBC32 is 12.2, and in DBC26 is 9.12. We chose these five bipolar cells to analyze cone synaptic gain for two reasons. 1) These cells exhibit high sensitivity to 500-nm light steps among mixed cells in Table 2, with the more negative log
values, and thus their relative cone/rod synaptic inputs should be among the lowest. If these cells exhibit substantial cone inputs, other bipolar cells with higher log
values should have even higher cone/rod input ratios. 2) Because of their high light sensitivity, relatively large voltage responses could be used in these bipolar cells for linear subtraction experiments. In bipolar cells of the tiger salamander retina, linear addition (as illustrated in Fig. 5) and linear subtraction (as illustrated in Fig. 6) are valid only when the rod and cone responses are small (within their linear response-intensity ranges: ~1.5 mV below the dark potentials, see above). Bipolar cells with high light sensitivity exhibited 10-20 mV responses to light stimuli, which elicited 0.3-1 mV rod or cone responses. Such large bipolar cell responses allowed reasonably accurate computer-assisted waveform subtraction for this set of experiments. It is evident from the results described above that the cone inputs in the mixed bipolar cells when stimulated with 750 nm light are quite high. The voltage gains of the cone input synapses are very close to the voltage gains of the rod input synapses (compare the gain values given above for bipolar cells HBC03, DBC26, HBC29, DBC32, and HBC35 with the second set of gain values in Table 3 for these 5 cells). We used the second set of gain values in Table 3 for comparison because it was estimated by the ratios of bipolar cell responses to 1.04 mV (the first set used 0.11 mV) of rod response, whereas the gain values in this section were obtained by the ratios of bipolar cell responses to 0.87 mV of cone response). From these results, one can conclude that mixed bipolar cells in dark-adapted tiger salamander retina make synaptic contacts with both rods and cones. When these bipolar cells are stimulated with 500 nm lights, their responses are mediated primarily by rods, because they reach saturation at intensities far below the response threshold of the cones. When they are stimulated by 750 nm lights, on the other hand, their responses are mediated by both rods and cones, and the two synaptic inputs have comparable voltage gains.

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| FIG. 6.
Linear subtraction of bipolar cell light responses. Voltage responses of a rod, a cone, and a HBCM (cell HBC29 in Table 2) to 0.5-s 750 nm/ 2.87 and 500 nm/ 7.67 light steps are given (left and middle). Difference responses of these 2 columns (obtained by computer subtraction, see METHODS) are given at right (750 nm/ 2.87-500 nm/ 7.67).
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DISCUSSION |
Mixed and cone-driven bipolar cells in dark-adapted retinas
In this article, we present a systematic study on the response amplitude, sensitivity, waveform, and the spectral properties of rods, cones, and bipolar cells in dark-adapted tiger salamander retinas. One major difference between our results and previous studies is that the relative sensitivity span of bipolar cells reported in this article extends over 6 log units, whereas other studies showed a much narrower sensitivity span (Capovilla et al. 1987
; Thibos and Werblin 1978
; Werblin 1977
). We attribute this difference to the use of infrared illumination during the dissection and in the microscope. The infrared instruments (cutoff wavelength near 850 nm) allow total dark adaptation, and we found that the sensitivity of rods and mixed bipolar cells with infrared are ~1.5-2 log units higher than that when red light is used during dissection and recording (Wu 1987
).
Functional implications of the wide sensitivity span of dark-adapted bipolar cells will be discussed in a subsequent section. Results described in this article also confirm our previous finding that bipolar cells in dark-adapted tiger salamander retina fall into two groups (Hensley et al. 1993
; Yang and Wu 1993
), one receives mixed inputs from rods and cones and the other is driven by cones. Several pieces of new information also are provided. 1) The DBCMs and HBCMs exhibit a wider ranger of response sensitivity than the DBCCs and HBCCs, and the log
values span over 2.5 log units along the intensity axis (Fig. 1B). Because the responses of these cells are mediated predominately by rods, and there is only one type of rods in the tiger salamander retina (Attwell et al. 1984
; Lasansky 1973
), it is not certain how the rods with small sensitivity variation (Fig. 1A) mediate postsynaptic responses in bipolar cells of such large sensitivity variation. We do not think that the sensitivity variation in bipolar cells is caused by light adaptation. This is because that there is no correlation between the state of light adaptation and the bipolar cell sensitivity (1st section in RESULTS): many bipolar cells with higher sensitivities were recorded under more light-adapted conditions than bipolar cells recorded in more dark-adapted retinas, and two bipolar cells recorded simultaneously had different sensitivity. One possible mechanism is that various rods may have different types of calcium channels with different activation voltage ranges. Our preliminary results have suggested rods in the tiger salamander retina have L- and N-type calcium channels (Wu et al. 1996
). The exact mechanisms of how these channels mediate bipolar cell responses are under investigation. 2) The DBCMs and HBCMs exhibit a wider variation of maximum response amplitude than the DBCCs and HBCCs (Fig. 1B). There is no systematic correlation between the maximum response amplitude, response sensitivity (log
) and state of retinal adaptation, although the DBCMs and HBCMs with the highest sensitivities tend to have large response amplitudes. We have plotted the bipolar cell responses in normalized V-log I scale (not shown in this paper); the log
values show similar spread along the intensity axis. We think the response amplitude variations in Fig. 1B reflect variation of DBCMs and HBCMs under physiological conditions, although we cannot rule out recording condition and electrode-induced membrane resistance change as contributing factors for such variation. 3) Although the vast majority of bipolar cells in dark-adapted retinas fall into two groups (the log
values of DBCMs and HBCMs are between
8.11 and
5.54, and those of the DBCCs and HBCCs are between
3.45 and
2.32, Table 2 and Fig. 1B), in a few instances we recorded bipolar cells with log
values lying between the two groups. Because we only recorded four such bipolar cells and only one of them has maximum amplitude >5 mV (HBC41 in Table 2 and dotted curve in Fig. 1B), we think these cells constitute a small portion of bipolar cells in the tiger salamander retina. Their function and relative rod/cone inputs are not certain. 4) The mixed bipolar cells receive substantial inputs from cones when they are stimulated with long wavelength light. By the use of linear subtraction method, we have shown that the voltage gains of the cone synapses made on these cells are of similar values as the rod synapses. This result suggests that this group of bipolar cells make synaptic contacts with both rods and cones, a notion that is consistent with the anatomic results of the tiger salamander retina (Lasansky 1973
). When these bipolar cells are stimulated by short-medium wavelength (or white) lights, their responses are mediated primarily by rods because rods are 2-3 log units more sensitive to these lights than cones (Yang and Wu 1996
), and the voltage gain of the rod-DBCM and rod-HBCM synapses are high (Table 2 and Fig. 4). Consequently responses of these cells to short-medium wavelength (or white) lights reach saturation at intensities below the response threshold of the cones (Fig. 1). Therefore the DBCM and HBCM responses under most stimulus conditions (with the exception of stimulus light of wavelength >650 nm) are driven by rods, even though these cells make synaptic contacts with both rods and cones. 5) The cone-driven bipolar cells, DBCCs and HBCCs, exhibit smaller variation in both response sensitivity and response amplitude (Table 2 and Fig. 1B) than the mixed bipolar cells. These bipolar cells receive inputs only from cones because when rods alone are stimulated by dim 500 nm lights, they give no responses. They respond to light stimuli only when the light intensity is bright enough to elicit cone responses (Figs. 1 and 3). Additionally, the spectral sensitivities of the cone-driven bipolar cells follow the spectral sensitivity curve of the cones very closely (Fig. 2). Therefore the DBCCs and HBCCs in dark-adapted tiger salamander retina serve as relays that convey pure cone signals to the inner retina.
Response sensitivity and voltage gain of rod- and cone-bipolar cell synapses
In this article, we have used two parameters to determine the light sensitivity of rods, cones and bipolar cells. The first is the relative sensitivity defined as the log light intensity that elicits half-maximal response (log
), and the second is the step sensitivity, SS, defined as the voltage response divided by the absolute intensity of light steps near the dark membrane potential. The relative sensitivity log
gives the relative operating range of the cell along the light intensity axis, and the step sensitivity gives the absolute sensitivity of the cell for small responses. We determine the log
values by fitting response data points with Eq. 2 and estimate the step sensitivities of rods, cones, and bipolar cells by using their responses to
8.3/500 nm light steps. The step sensitivity of the rod, SS(rod) is 1.07 mV photon
1 µm2 s and that of the cone, SS(cone) is 0.00146 mV photon
1 µm2 s. These values are similar to those obtained in earlier studies on the amphibian and turtle retinas (Baylor and Hodgkin 1973
; Diamond and Copenhagen 1995
; Yang and Wu 1996
). The step sensitivity of mixed bipolar cells for rod inputs, SS(rod-DBCM or rod-HBCM) ranges from 1.22 to 51.82 mV photon
1 µm2 s, which are of the same order of magnitude as the bipolar cell sensitivity for rod inputs reported in an earlier study in which no distinction between rod- and cone-driven bipolar cells is made (Capovilla et al. 1987
). The step sensitivity of cone-driven bipolar cells for cone inputs, SS(cone-DBCC or cone-HBCC) ranges from 0.0000438 to 0.00201 mV photon
1 µm2 s. Therefore, in dark-adapted tiger salamander retinas, the step sensitivities of bipolar cells distribute over 6 log units. This finding extends the bipolar cell sensitivity range by ~3 log units from the previous bipolar cell data in which only rod inputs are studied (Capovilla et al. 1987
). The functional implication of such wide bipolar cell sensitivity distribution will be discussed in next section.
We also have estimated the chord voltage gains of the rod- and cone-bipolar cell synapses in dark-adapted tiger salamander retinae. We list two sets of gains in Table 3, with the first obtained from rod or cone responses ~0.1 mV below their dark potentials and the second set from responses ~1 mV below the dark potentials. The first set of gains is three to five times higher than the second set; this is consistent with the finding that the input-output relations of the photoreceptor-bipolar cell synapses are nonlinear with the highest gain near the photoreceptor dark potential (Belgum and Copenhagen 1988
; Falk 1989
; Yang and Wu 1993
). Additionally, from the results shown in Fig. 4, it is evident that the log(voltage gain) of the rod-DBCM, rod-HBCM, cone-DBCC, or cone-HBCC synapses is approximately proportional to the relative sensitivity (log
) of the bipolar cells. The proportional constant,
, is about
0.5 for the rod-DBCM and rod-HBCM synapses and
0.9 for the cone-DBCC and cone-HBCC synapses. In other words, for each log unit increase of bipolar cell sensitivity (more negative log
), there is a 0.5 log unit(100.5 = 3.16)-fold increase of voltage gain in the rod input synapse; and a 0.9 log unit(100.9 = 7.94)-fold increase of voltage gain in the cone input synapse. Therefore bipolar cells with higher relative light sensitivity have higher voltage gains at their photoreceptor input synapses, which is consistent with a theoretical model (Attwell 1990
). However, it is not clear whether the higher voltage gains are mediated by more synaptic contacts from photoreceptors or by higher synaptic efficacy at each synaptic contact. A systematic electron microscopic study on physiologically identified bipolar cells in this retina is needed to clarify this question.
It has been assumed that DBCs in the retina have higher synaptic gains than the HBCs because DBCs use metabotropic glutamate receptors (L-AP4 receptors associated with a cGMP second messenger cascade), whereas HBCs use ionotropic glutamate receptors, and the glutamate-gated channels in DBCs are closed in darkness whereas those in HBCs are open (Falk 1989
). Our results in this article do not support this assertion. In Figs. 1B and 3 and Tables 2 and 3, there is no obvious difference in response amplitude and voltage gain between the DBCs and HBCs. It appears that both types of bipolar cells have similar ranges of voltage gains at their photoreceptor input synapses.
In this study, by using linear subtracting method, we selected five mixed bipolar cells and estimated their cone synaptic gains under dark-adapted conditions. Results obtained indicate that for each bipolar cell, the voltage gain of the cone input synapse is very close to the voltage gain of the rod input synapse. This is in sharp contrast to the results in Table 3 and Fig. 4, which show that the voltage gains of the rod-DBCM and rod-HBCM synapses are ~10 times higher than the voltage gains of the cone-DBCC or cone-HBCC synapses. These results indicate that when rods and cones make synapses on the same bipolar cell (either DBCM or HBCM), their synaptic gains are compatible; but when they make synapses on different types of bipolar cells (mixed or cone-driven bipolar cells), their synaptic gains are very different. From this one can conclude that the difference in voltage gain between rod-mixed bipolar cell synapses and cone-cone-driven bipolar cell synapses is probably mediated by postsynaptic factors in bipolar cells not by differences in the presynaptic rod and cone outputs. In a recent study, we have shown that the steady-state glutamate-induced currents in mixed bipolar cells are substantially larger than that in cone-driven bipolar cells (Wu et al. 1996
). If the voltage gains of the photoreceptor input synapses are related to the steady state glutamate current in bipolar cells, our result suggests that difference in glutamate receptor in the two types of bipolar cells may be a contributing factor for the different synaptic gains.
Functions of the mixed and cone-driven bipolar cells
It has been known for sometime that the dynamic range of retinal bipolar cells is much narrower than that of photoreceptors (Thibos and Werblin 1978
; Werblin 1971
, 1977
). What is unclear is how cells of such narrow operation range encode rod and cone responses of much wider intensity spans. One mechanism of extending bipolar cell operation range was proposed by Thibos and Werblin (1978)
, who showed that the V-log I curves of bipolar cell cells shifted to the right along the log I axis by background light. It is still uncertain, however, how bipolar cells under dark-adapted conditions encode rod and cone responses of much wider dynamic range. We have shown in this article that the relative light sensitivity (log
) of bipolar cells in dark-adapted tiger salamander retinas spreads over 6 log units of light intensity, which almost covers the entire operation range of rods and cones (compare Fig. 1, A and B), although the average dynamic range (2.56/N, see METHODS) of individual bipolar cells is only ~2.61 log units. Each bipolar cell covers a fraction of the rod or cone operation range, and thus the entire rod and cone light responses are encoded piecewise by various bipolar cells. The narrow dynamic range and wide spread of log
values of bipolar cells allow higher resolution for dim photoreceptor signals and avoid saturation for large photoreceptor signals. For dim light, which gives small rod signals, bipolar cells with high relative sensitivities (more negative log
) and high-voltage gains are used so that small rod responses can be amplified and clearly resolved beyond the noise level. For brighter light, which gives larger signals, bipolar cells with high sensitivity (and high-voltage gain) reach saturation so they cannot be used to resolve these signals. Other bipolar cells with lower sensitivity (and lower gain) are used, and they reach saturation when even brighter light gives even larger photoreceptor signals. Then other bipolar cells with even lower sensitivity are used to encode these photoreceptor signals. Consequently, by dividing light responses into many segments along the light intensity axis, bipolar cells encode photoreceptor signals with higher amplification for small rod responses and lower amplification for large photoreceptor responses.
 |
ACKNOWLEDGEMENTS |
We are indebted to F. Gao and S. Singh for assistance in figure and table preparations.
This work was supported by grants from the National Eye Institute (EY-04446), the Retina Research Foundation (Houston), and Research to Prevent Blindness, Inc.
 |
FOOTNOTES |
Present address of X.-L. Yang: Shanghai Institute of Physiology, Chinese Academy of Sciences, 320 Yue Yang Rd., Shanghai 200031, China.
1
Derivation of Eq. 1 shown above depended on the photoreceptor outer segment being aligned with the light path. Our recordings were carried out under visual control so that we could see the tips of photoreceptor outer segments very well. We routinely picked the areas where a large number of photoreceptors were intact, the retina was flat, and the outer segments were perpendicular to the focal plane of the objective. Because stimulus light was delivered by the objective lens of the microscope, we are quite confident that the incident light was parallel to the axes of photoreceptors.
Address reprint requests to S. M. Wu.
Received 15 November 1996; accepted in final form 1 July 1997.
 |
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