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The Journal of Neuroscience, June 15, 2000, 20(12):4462-4470
Functional Architecture of Synapses in the Inner Retina:
Segregation of Visual Signals by Stratification of Bipolar Cell
Axon Terminals
Samuel M.
Wu,
Fan
Gao, and
Bruce R.
Maple
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas
77030
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ABSTRACT |
We correlated the morphology of salamander bipolar cells with
characteristics of their light responses, recorded under voltage-clamp conditions. Twelve types of bipolar cells were identified, each displaying a unique morphology and level(s) of axon terminal
stratification in the inner plexiform layer (IPL) and exhibiting light
responses that differed with respect to polarity, kinetics, the
relative strengths of rod and cone inputs, and characteristics of
spontaneous EPSCs (sEPSCs) and IPSCs. In addition to the well
known segregation of visual information into ON and OFF channels along
the depth of the IPL, we found an overlying mapping of spectral
information in this same dimension, with cone signals being transmitted
predominantly to the central IPL and rod signals being sent
predominantly to the margins of the IPL. The kinetics of bipolar cell
responses correlated with this segregation of ON and OFF and of rod and cone information in the IPL. At light offset, rod-dominated cells displayed larger slow cationic current tails and smaller rapid overshoot responses than did cone-dominated cells. sEPSCs were generally absent in depolarizing bipolar cells but present in all
hyperpolarizing bipolar cells (HBCs) and larger in rod-dominated HBCs
than in cone-dominated HBCs. Inhibitory chloride currents, elicited
both at light onset and light offset, tended to be larger for
cone-dominated cells than for rod-dominated cells. This orderly segregation of visual signals along the depth of the IPL simplifies the
integration of visual information in the retina, and it begins a chain
of parallel processing in the visual system.
Key words:
retina; bipolar cells; light-evoked postsynaptic
currents; axon terminal stratification; ON and OFF channels; rod and
cone inputs; parallel information processing
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INTRODUCTION |
In the visual system, the projection
of light-evoked signals from the eye to the brain is organized into
parallel routes; different classes of retinal ganglion cells carry
signals of different qualities, such as color, contrast, and form, to
segregated regions in highly organized three-dimensional structures of
the lateral geniculate nuclei and the visual cortex (Enroth-Cugell and
Robson, 1966 ; Hubel and Wiesel, 1977; Hubel and Livingstone, 1987).
While the retina represents information about positions within the
visual world in two dimensions, it also appears to use the orthogonal third dimension (the depth of the retina) to represent qualities of
visual stimuli. Anatomical studies suggest that the inner plexiform layer (IPL) of the retina has a highly elaborate sublaminar
organization; the axon terminals of bipolar cells and the dendrites of
amacrine cells and ganglion cells display widely diverse morphologies, with processes stratifying at many different levels of the IPL (Ramon y
Cajal, 1893; Boycott and Dowling, 1969; Kolb, 1982). In mammalian
retinas, for example, 1 type of rod bipolar cell and 9-10 types of
cone bipolar cells with distinguishable morphology and levels of axon
terminal stratification have been identified (Boycott and Wassle, 1991;
Euler and Wassle, 1995), but the light responses of these cells have
not been clearly described. Furthermore, a functional segregation of
ON-center and OFF-center bipolar cell (also known as "depolarizing"
and "hyperpolarizing" bipolar cells, or DBCs and HBCs,
respectively) inputs to the IPL has been well established across many
species; the on-center cells synapse at the proximal levels of the IPL
(sublamina B), and the off-center cells synapse at the distal levels of
the IPL (sublamina A) (Famiglietti and Kolb, 1976; Nelson et al.,
1978).
Bipolar cells of the tiger salamander retina have been shown previously
to vary greatly with respect to light response sensitivity and kinetics
(Hensley et al., 1993; Yang and Wu, 1997), but cell morphology was not
routinely examined in these experiments. In this study, we investigated
the light responses of morphologically identified bipolar cells under
voltage-clamp conditions in salamander retinal slices. The axon
terminal morphology of these cells was compared with a number of light
response characteristics: the relative strength of rod and cone inputs,
the polarity, amplitude, and kinetics of excitatory and inhibitory
light responses, and the spontaneous EPSCs and IPSCs (sEPSCs and
sIPSCs). On the basis of this comparison of axon terminal morphology
and light response characteristics, 12 distinct types of bipolar cells
were identified, each of which transmits a different set of light
response qualities to the third-order retinal neurons by synapses made
at different levels of the IPL.
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MATERIALS AND METHODS |
Larval tiger salamanders (Ambystoma tigrinum)
purchased from Charles D. Sullivan (Nashville, TN) and Kons Scientific
(Germantown, WI) were used in this study. The procedures of dissection,
retinal slicing, and recording were described in previous publications (Werblin, 1978; Wu, 1987). Salamanders were dark adapted for 3 hr
before dissection, and dissection and electrode placement were performed under dim red light. Oxygenated Ringer's solution was introduced continuously to the superfusion chamber, and the control Ringer's solution contained 108 mM NaCl, 2.5 mM KCl, 1.2 mM
MgCl2, 2 mM
CaCl2, and 5 mM HEPES,
adjusted to pH 7.7. All chemicals were dissolved in control Ringer's
solution. A photostimulator was used to deliver light spots (500-600
µm in diameter) to the retina via the epi-illuminator of the
microscope. The intensity of unattenuated (log I = 0)
500 nm light (10 nm bandwidth), measured with a radiometric detector
(United Detector Technology, Santa Monica, CA), was 2.05 × 107
photons·µm 2·sec1.
Voltage-clamp recordings were made with an Axopatch 200A amplifier
connected to a DigiData 1200 interface and pClamp 6.1 software (Axon
Instruments, Foster City, CA). Patch electrodes of 5 M tip
resistance when filled with internal solution containing 118 mM Cs methanesulfonate, 12 mM CsCl, 5 mM EGTA, 0.5 mM CaCl2, 4 mM ATP, 0.3 mM GTP, 10 mM Tris, and
0.8 mM Lucifer yellow, adjusted to pH 7.2 with CsOH, were
made with Narishige or Kopf patch electrode pullers. The chloride
equilibrium potential (ECl) with this internal solution was approximately  60 mV. Estimates of the liquid junction potential at the tip of the patch electrode before seal formation varied from 9.2 to 9.6 mV. For simplicity, we corrected all holding
potentials in this paper by 10 mV.
Cell morphology was visualized via the use of Lucifer yellow
fluorescence, and morphometry was performed with the aid of an eyepiece
micrometer. The level at which axonal processes stratified in the IPL
was characterized by the distance from the processes to the distal
margin of the IPL. This distance was expressed in inner plexiform
layer units (IU), in which the thickness of the entire IPL was
defined as 1.0 IU (see Fig. 1B). We selected for bipolar cells with somas situated beneath the surface of the slice. These cells usually had relatively intact axon terminals, but in cases
in which the axons were severed or the axon terminals were badly
deformed, the data were discarded. The anatomical data presented
(see Figs. 2, 3) include data from similar patch-clamp experiments not described in this paper.
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RESULTS |
Morphological diversity of bipolar cells in the
salamander retina
Figure 1 shows a fluorescence
photograph of a bipolar cell in a retinal slice (Fig.
1A) and a sketch made while viewing the same cell at
different focal planes (Fig. 1B). Typical bipolar cell features (labeled in Fig. 1B) include a soma
(cell body) centered in the distal half of the inner nuclear
layer, a Landolt club extending into the outer nuclear layer,
dendrites branching in the outer plexiform layer, and an axon with
terminal processes ramifying laterally within the IPL. The bipolar cell
of Figure 1 is an example of what we termed a "monostratified"
cell, i.e., a cell with axon terminals that ramified in a very planar
manner within a single narrow level of the IPL. Although a majority
(59%) of the 343 cells studied were monostratified, two other classes of axon terminal morphology were observed. Some bipolar cells (24%)
had "pyramidally branching" axons; i.e., although their axonal
processes terminated at a narrow level within the IPL, they began
branching at more distal levels of the IPL (see Fig. 5, cell types 5, 8, 12). In addition, some cells were "multistratified"; i.e., their
axon terminals were stratified at two or three distinct levels within
the IPL (e.g., see Fig. 5, cell types 3, 4, 6, 11). Bistratified and
tristratified cells accounted for 17 and 1%, respectively, of the
bipolar cells studied.
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Figure 1.
A, A fluorescence photograph of a
bipolar cell in a retinal slice filled with Lucifer yellow.
B, A sketch made while viewing the same cell at
different focal planes. Depth within the IPL was characterized in inner
plexiform layer units, with the INL margin
corresponding to 0.0 IU and the ganglion cell margin to 1.0 IU.
A, Axon; AT, axon terminal;
C, cone; CB, cell body; D,
dendrite; G, ganglion; GCL, ganglion cell
layer; INL, inner nuclear layer;
LC, Landolt club; OPL, outer plexiform
layer; PRL, photoreceptor layer; R, rod;
WAT, axon terminal field width;
WD, dendritic field width.
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The spatial distribution of the bipolar cell axon terminals within the
IPL is summarized in Figure 2, which
shows frequency histograms for the level of ramification (or
termination in the case of pyramidally branching cells) for each of
these three general morphological classes of axon terminals.
Monostratified cells appeared to terminate continuously throughout the
depth of the IPL, but the peaks in Figure 2A suggest
a nonuniform distribution of axon termination in the IPL. The
distribution for pyramidally branching cells (Fig.
2B) was also decidedly nonuniform, with peaks near
0.5 and 0.85 IU (IU is defined in Fig. 1B and
Materials and Methods). The multistratified cells (Fig. 2C)
ramified mostly in sublamina A [defined as 0-0.55 IU, on the basis of
dendritic glutamate responses (Maple and Wu, 1996) and light responses
discussed in this paper]. Seventy-two percent of bistratified bipolar
cells ramified exclusively in sublamina A, whereas <4% of the
bistratified cells ramified exclusively in sublamina B (0.55-1.0 IU).
All three tristratified cells observed had two levels of ramification
in sublamina A and one in sublamina B. It is important to note that the
distributions presented in Figure 2 could be influenced by sampling
bias, so they do not necessarily reflect the actual relative frequencies of different bipolar cell types in the salamander retina.
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Figure 2.
Frequency histograms for the levels of bipolar
cell axon terminal ramification within the IPL. A, Cells
with axon terminals ramifying in a single stratum (monostratified).
B, Cells with pyramidally branching axon terminals.
C, Cells with axon terminals ramifying in more than one
strata (multistratified). Histograms were plotted against the level of
axon terminal endings in inner plexiform layer units (defined in Fig.
1B and Materials and Methods) with a bin width of
0.05 IU. On the basis of light responses (see Fig. 5) and dendritic
glutamate responses (Maple and Wu, 1996), sublamina A is defined as
0.0-0.55 IU, and sublamina B is defined as 0.55-1.0 IU.
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The widths of the dendritic field (WD) and
axon terminal field (WAT), as defined
in Figure 1B, were also characterized for most cells,
and these data are presented as scatter plots in Figure 3, A and C,
respectively. (For simplicity, the data for multistratified cells are
not included in Fig. 3.) The dendritic and axon terminal field widths
were both highly variable, even for cells with otherwise similar
morphology. There was a tendency, however, for
WAT to be significantly larger for
cells ramifying near either margin of the IPL than for cells ramifying
more centrally, as is evident in the mean width histogram of Figure
3D. Such a striking pattern was not observed for the
dendritic field widths (Fig. 3C), but there was a
significant tendency for WD to be larger
for cells ramifying in the distal half of sublamina A than for those
terminating in the proximal half of sublamina A. Averaged over all
cells, the mean WD (± SD) was
58 ± 21 µm, and the mean WAT
was 67 ± 25 µm.
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Figure 3.
A, C, Scatter plots of
WD (defined in Fig.
1B; A) and
WAT (C) against the
level of the axon terminal ramification in the IPL (in inner plexiform
layer units). B, D, The mean (± SE)
WD and WAT are
shown in B and D, respectively.
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A most conservative interpretation of the data in Figure 2 is that the
salamander retina possesses at least nine types of bipolar cells (four
monostratified types, two pyramidally branching types, two bistratified
types, and one tristratified type). The data suggest, however, that
more types than these exist. In slices with good structure it is easy
to distinguish a difference between monostratified cells that ramify at
0.05 and 0.20 IU, for instance, so it would seem likely that these
represent different cell types. On the other hand, in the region of
0.0-0.3 IU, there is only a single peak in the frequency histogram of
Figure 2A, so from axon morphology alone, it is not
clear just how many different types of bipolar cells may ramify in this
region. The dendritic and axon terminal field widths do not aid much in
distinguishing cell types; although there is a significant difference
in mean axon terminal field width for cells ramifying near 0.05 IU
versus those terminating near 0.20 IU, the widths are not clustered in any way suggesting distinctly different cell types.
Photoreceptor inputs to bipolar cells
Figure 4 compares light responses of
a DBC with responses of an HBC. In both cases the photoreceptor
inputs were isolated by holding the cell at
ECl (thus eliminating any inhibitory
currents that might be generated at chloride-mediated synapses from
amacrine cells and interplexiform cells). Under these conditions the
DBCs, which give rise to the ON pathway of the visual system, displayed inward current responses ( IC; Fig.
4A, the light-evoked cation current,). In contrast,
the HBCs, which mediate the OFF pathway, exhibited an outward
IC (Fig. 4B). HBCs
could also be distinguished from DBCs on the basis of the presence of
spontaneous sEPSCs (Maple et al., 1994; Wu and Maple, 1998), as
illustrated in the Figure 4B inset. In darkness the
HBCs displayed a very high frequency of sEPSCs, which are responsible
for the prominent current noise visible in the records of Figure
4B. The sEPSCs decreased in frequency during a light
stimulus, and this is reflected in Figure 4B as a
decrease of current noise during light stimulation. Although the mean
amplitude of the sEPSCs appeared to vary among different HBC
subtypes, sEPSCs were observed in all HBCs. On the other hand, sEPSCs
were never observed in DBCs, with the exception of two types of
multistratified cells that will be discussed below.
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Figure 4.
A, B, Current responses of a DBC
(A) and an HBC (B) to 500 and 700 nm light steps of various intensities (labeled in log units of
attenuation on the left of each current
trace). C, The response-intensity
relations for these current responses. For the criterion response of 10 pA marked by the horizontal dashed
line, S for the DBC is 0.81 and for
the HBC is 2.60. Inset in B, One of the
sEPSCs that contributed to the very noisy signals observed in this
cell.
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Cone photoreceptors in the tiger salamander retina exhibit similar
sensitivity to red and green light, but the rod photoreceptors are much
more sensitive to green than to red light (Yang and Wu, 1989, 1996).
Consequently, the relative strength of rod and cone inputs to bipolar
cells could be characterized by comparing response-intensity relations
for 500 and 700 nm light stimuli, as demonstrated in Figure 4.
Response-intensity curves for data from a DBC (Fig. 4A) and an HBC (Fig. 4B) are shown
in Figure 4C. Comparing the curves for 500 and 700 nm
stimuli, it is apparent that there is a greater separation of the two
curves along the intensity axis for the HBC data (denoted by
open symbols) than for the DBC data (denoted by
filled symbols), suggesting that this HBC
received stronger rod input than did the DBC. The separation of the
curves was quantified by a measure termed the "spectral difference"
(S), defined as S = S700 S500, where
S700 and
S500 correspond to intensities of 700 and 500 nm light that yield responses equal in amplitude, for a small
criterion amplitude (Yang and Wu, 1996). Measured at a criterion
amplitude of 10 pA, as illustrated in Figure 4C, the
spectral difference was 0.8 log units for the DBC and 2.6 log units for
the HBC. Because S is ~0.1 log units for cones and
~3.4 log units for rods (Yang and Wu, 1990), we concluded that the
DBC of Figure 4 was cone dominated, whereas the HBC was relatively rod
dominated. Overall, a wide range of rod and cone dominance was observed
both for DBCs (S = 0.2-2.9) and for HBCs (S = 0.3-3.1).
By combining this spectral difference data with data concerning axon
terminal morphology, light response polarity, the kinetics of
excitatory and inhibitory currents at light onset and offset, and the
spontaneous postsynaptic currents, we were able to define 12 different
classes of bipolar cells, as depicted in Figure
5A. The levels of axon
terminal ramification in the IPL (in inner plexiform layer units), the
mean (± SE) values of the spectral difference
(S), and the amplitude of the light-evoked excitatory cation current (IC) and inhibitory
current (ICl, the light-evoked chloride current recorded at 0 mV, near the reversal potential for
photoreceptor inputs) at light onset (ON) and offset (OFF) are given in
Figure 5B. (Note that the cells included in these averages
constitute a subset of the cells described in Fig. 2, i.e., the subset
for which light response data were obtained as described in this
paper.) Additionally, the frequency of large sEPSCs and sIPSCs
in each class of bipolar cells was estimated on an approximate scale (0 to ***) in Figure 5B. The 12 classes defined here represent
types that were clearly distinguishable by two or more of
the parameters listed in Figure 5B. These parameters will now be discussed with respect to how visual signals are mapped in
the IPL.
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Figure 5.
A, Morphology (sketches of Lucifer
yellow-filled cells in retinal slices; top row) and
light-evoked current responses (to a 500 nm stimulus of 1.3 log unit
intensity; bottom row) recorded under
voltage-clamp conditions at various holding potentials. For all cells,
EC = 0 mV and
ECl = 60 mV, and thus
IC and sEPSCs were measured at 60 mV,
and ICl and sIPSCs were measured at 0 mV.
Vertical calibration bar (bottom left):
100 pA for type 1-11 bipolar cells; 200 pA for the type 12 bipolar
cell. B, Top, Summary of the levels of
axon terminal ramification in the IPL (in inner plexiform layer units),
the average (± SE) values (N, number of cells averaged)
of the relative spectral difference (S) and the
amplitude (in pA) and polarity (+, outward; , inward) of the
light-evoked excitatory current at light onset
(ICON), the ratios of excitatory
current response at light offset/onset
(ICOFF/ICON)
for off overshoot (OS) and tail
(Tail) responses, the ratios of light-evoked
inhibitory ON and OFF current response/excitatory ON current response
(IClON/ICON,
IClOFF/ICON),
and the approximate frequency (0, absent; *, low; **, medium; and ***,
high) of sEPSCs and sIPSCs for the 12 classes of bipolar cells.
Bottom, Illustrations of how
ICON,
ICOFF(OS),
ICOFF(Tail),
IClON, and
IClOFF of the HBC and the DBC were
measured. For responses that had no cationic current tail of the same
polarity as ICON,
ICOFF(Tail) was assigned a value of
zero. The values of ICOFF(OS),
ICOFF(Tail),
IClON, and
IClOFF were normalized relative to the
value of ICON before averaging.
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The segregation of ON-center and OFF-center bipolar cell (DBC and
HBC) outputs in the IPL
Among the bipolar cells that ramified exclusively in sublamina A
of the IPL (Fig. 5, types 1-5), all exhibited outward light-evoked current (IC) near
ECl; i.e., they were HBCs. Likewise,
all cells that ramified exclusively in sublamina B (types 7-10) were
DBCs, displaying inward IC near
ECl. These results are in agreement with the general observation that the OFF-center and ON-center pathways
are segregated into sublamina A and sublamina B, respectively (Famiglietti and Kolb, 1976; Nelson et al., 1978). However, we observed
three types of bipolar cells that ramified in both sublamina A and
sublamina B. One of these was a class of pyramidally branching cell
(type 12), with axonal processes that began branching in sublamina A
but terminated at a proximal level of sublamina B (0.8-0.9 IU). These
cells appeared to be purely DBCs, on the basis of an inward
IC at
ECl and the absence of sEPSCs. Another
class of cell (type 11) that stratified in both sublamina A and
sublamina B appeared to be a hybrid, possessing both ON-center
(sign-reversing) and OFF-center (sign-preserving) cationic conductance
mechanisms at photoreceptor synapses. These cells, which (like
HBCs) exhibited sEPSCs , also displayed a net inward
IC at
ECl, (like DBCs). Curiously, in
previous experiments conducted in bright light, cells with this
distinctive morphology exhibited a cationic conductance increase in
response to dendritic application of glutamate (Maple and Wu, 1996);
furthermore, one such cell was studied in an experiment in which the
rod network was depolarized with a second patch electrode, and this
stimulus also elicited a cationic conductance increase in the bipolar
cell, as would be expected for an HBC [our unpublished observation from experiments described in Maple et al. (1994)]. It is
not clear why these cells appeared to be DBCs in some experiments and
HBCs in others, but it could conceivably be related to the different
states of light adaptation in these experiments. A type of
tristratified cell (type 6) also appeared to possess both ON and OFF
conductance mechanisms. These cells normally appeared to be HBCs, with
sEPSCs and an outward IC at
ECl, but in the presence of 100 µM picrotoxin the light responses of these
cells were converted to an inward (DBC-like) current (data not shown). Thus, it seems there may be a perfect correlation between the sign of
photoreceptor inputs received by bipolar cells and the level(s) at
which the bipolar cells' axonal processes terminate in the IPL; cells
with processes terminating exclusively in sublamina A are excited by
darkness (OFF-center), cells with axons terminating exclusively in
sublamina B are excited by light (ON-center), and cells with axon
terminations in both sublamina A and sublamina B receive both ON-center
and OFF-center inputs.
Gradients of rod and cone dominance in the IPL
The spectral difference data presented in Figure 5 show a general
trend for rod-dominated bipolar cells to ramify near the margins of the
IPL and for cone-dominated cells to ramify more centrally in the IPL.
This correlation was particularly strong for the HBCs, with the most
rod-dominated cells (types 1 and 2) being monostratified in the
distal half of sublamina A (sA1, 0.0-0.3 IU) and
the most cone-dominated cells (type 5) being monostratified or
pyramidally branching within the proximal half of sublamina A
(sA2, 0.3-0.55 IU). Even within
sA1 a gradient of rod-cone dominance was
observed, with the cells ramifying in the distal half of
sA1 (type 1) being the most rod dominated of all
bipolar cells observed and with cells ramifying in the proximal half of
sA1 (type 2) being slightly less rod dominated.
Cells that were bistratified within sublamina A displayed intermediate
values of S, but these could still be divided into two
different classes, on the basis of anatomy and spectral sensitivity.
The bistratified HBCs exhibited a wide range of axon terminal
morphologies, but spectrally they fell into two groups, which also
differed consistently with respect to their more proximal level of
ramification. Type 4 cells, with a proximal stratum at a depth of
0.45-0.55 IU, were more cone dominated than type 3 cells, whose most
proximal level of ramification was at 0.25-0.40 IU.
A similar, but less strict, gradient of rod and cone influence was
observed in sublamina B of the IPL. Following a margin to center
organization of rod and cone dominance, the most proximally ramifying
DBCs (type 10; 0.9-1.0 IU) were rod dominated, the most centrally
ramifying DBCs (type 7; 0.55-0.7 IU) were cone dominated, and cells
ramifying at intermediate levels were more mixed (types 8 and 9;
0.7-0.9 IU). On the other hand, the mixed cells fell into two
different classes that received more or less rod input (types 8 and 9, respectively), and among these there was no simple correlation between
S and the level of ramification. It seems that rod and
cone information is not segregated as simply for the ON-center pathways
of the retina as it is for the OFF-center pathways.
The kinetics of the photoreceptor inputs at light offset was also
consistent with these gradients of rod and cone dominance in the IPL.
Cone photoreceptors rapidly depolarize to a steady-state dark potential
at the cessation of a light stimulus, whereas rod photoreceptors
depolarize more slowly, taking seconds to reach a steady-state
potential after a bright stimulus (Yang and Wu, 1996). This was
reflected in the photoreceptor component of bipolar cell light
responses, as visible in Figure 5 for the traces at 60 mV
(ECl). At light offset the responses
of cone-dominated cells (those with a small S) were
dominated by a rapidly developing, strongly transient inward current
(in the case of HBCs) or a slightly less rapidly developing, mildly
transient outward current (in the case of DBCs). For HBCs this
transient tended to shoot beyond the prestimulus dark current level,
and the size of this overshoot [ICOFF(OS) in Figure 5,
relative to the size of the response to light onset] was
negatively correlated with S. The responses of
rod-dominated cells (those with a large S), on the other
hand, were dominated by a slowly developing inward current (in the case of HBCs) or outward current (in the case of DBCs). The size of this
slow-current tail [ICOFF(Tail) in
Figure 5, given relative to the response at light onset] was
positively correlated with S (with the exception of the
type 5 cone-dominated HBCs, which, as discussed below, displayed a
sizable tail). These observations are consistent with a general
tendency of cone-dominated bipolar cells to ramify more centrally in
the IPL than rod-dominated bipolar cells.
Rod- and cone-dominated HBCs could also be distinguished by
characteristics of the sEPSCs associated with their photoreceptor inputs (Maple et al., 1994; Wu and Maple, 1998). Rod-dominated HBCs
(types 1 and 2) were readily identified by the presence of large-amplitude sEPSCs. sEPSCs were also observed in the more cone-dominated HBCs (types 3-6), but they appeared to be much smaller
in mean amplitude. Quantitative analysis of the sEPSCs in HBCs is not a
simple matter, because they vary tremendously in amplitude, the
amplitude distributions are highly skewed toward the baseline noise,
and the distributions do not have peaks that stand out from the
baseline noise, even under very low-noise conditions (Maple et al.,
1994); furthermore, there is much superposition of the sEPSCs under the
dark-adapted conditions described in this paper. For these reasons, the
issue of sEPSC amplitude will not be quantitatively addressed here.
Instead, an approximate scale (0 to ***) was used in Figure
5B. We would like to emphasize that the rod-dominated HBCs
(types 1 and 2) could be easily and reliably distinguished from more
cone-dominated HBCs (types 3-6) on the basis of qualitative
examination of the noise associated with IC. As is visible in the
traces of Figure 5, the rod-dominated HBCs exhibited much
more noise (at ECl) and some much
larger sEPSCs (of up to 1 nS peak conductance) than did the
cone-dominated HBCs. This difference points to a functional segregation
of rod and cone information in the IPL.
Inhibitory inputs to bipolar cells
When held at 0 mV (near EC, the
reversal potential for cation currents generated at photoreceptor
synapses), most bipolar cells displayed outward current responses at
light onset and/or light offset. In cases in which these inhibitory
responses were very transient (e.g., Fig. 5, the onset response of cell
12 or the offset response of cell 5), they clearly reversed near
ECl, and it is likely that they were
generated by a chloride conductance increase. It was more difficult to
characterize the I-V properties of more sustained
inhibitory inputs, because these were masked by photoreceptor inputs at
holding potentials away from EC.
Nevertheless, the overall I-V characteristics of the light
responses suggested that a sustained chloride conductance increase
contributed to the onset response of many bipolar cells. Consider, for
instance, the responses to light onset for HBC types 1, 2, and 5 in
Figure 5. The responses of type 2 cells reversed near +20 mV,
considerably positive to the reversal potential for the sEPSCs, which
reversed near 0 mV (as do glutamate-activated currents in HBCs). This
is understandable if the light-induced cationic conductance decrease occurring at photoreceptor synapses was accompanied by a smaller conductance increase to an ion with a negative equilibrium potential (for instance, a chloride conductance increase at amacrine cell synapses). In the case of type 1 HBCs the light responses did not
reverse at all, and that is consistent with a chloride conductance increase that was comparable in magnitude with the cationic conductance decrease at photoreceptor synapses. Finally, for type 5 HBCs the light
responses did not reverse but became larger with increasingly positive
potentials, and this is consistent with a chloride conductance increase
that was larger than the accompanying cationic conductance decrease.
Because DBCs undergo a cationic conductance increase at light onset, a
simultaneous chloride conductance increase would be expected to make
the light response reverse negative to EC in these cells, and this was, in fact, observed. Where the reversal potential of DBC light responses differed from
EC, it was always negative to
EC (and positive to
ECl).
Figure 5B, top, summarizes the relative strengths of the
inferred chloride conductance increases at light onset
(IClON) and light offset
(IClOFF) for each of the 12 classes
of bipolar cells we have defined. Among the six classes of HBCs, the
mean values of both IClON and
IClOFF (relative to the magnitude
of IClON) were negatively
correlated with S; i.e., the inhibition at both light
onset and light offset was stronger for the cone-dominated cells than
for the rod-dominated cells. Among the DBCs, there was not, in general,
a strong correlation between either
IClON or
IClOFF and S, but
both ON and OFF inhibitions were stronger for the most cone-dominated
cells (type 7) than for the most rod-dominated cells (type 10).
Overall, the strength of these inhibitory inputs appeared to be more
closely related to axon morphology than to the value of
S, per se. The relative magnitude of
IClON tended to be largest among
bipolar cell types 4-7 and 12, all cells with ramifications near a
central region (0.4-0.7 IU) of the IPL. Similarly, IClOFF was largest in cells with
ramifications in sublamina A2 (0.3-0.55 IU).
A portion of the inhibition received by bipolar cells was mediated by
sIPSCs, which are thought to be generated at synapses from glycinergic
amacrine and interplexiform cells (Maple and Wu, 1998). Most bipolar
cells exhibited some sIPSCs, but, overall, this inhibition accounted
for only a small fraction of the total chloride current elicited by
light stimuli. This type of inhibition was particularly strong,
however, in the type 3 bistratified HBCs, which displayed strong bursts
of sIPSCs both at light onset and offset. On the other end of the
spectrum, very few or no sIPSCs were observed in type 5 HBCs and type
10 DBCs. Type 7 DBCs varied greatly with respect to sIPSC activity; in
some the sIPSCs contributed greatly to
IClOFF, and in others very few
IPSCs were observed. Further study of inhibitory inputs to bipolar
cells may lead to a division of type 7 cells into different subtypes.
| |
DISCUSSION |
ON-center and OFF-center channels
In agreement with previous studies of dendritic glutamate
responses (Maple and Wu, 1996), the light responses described here indicate that in the salamander retina, OFF-center bipolar cells make
output synapses in the most distal 55% of the IPL (sublamina A),
whereas ON-center bipolar cells synapse in the most proximal 45% of
the IPL (sublamina B). Sublamina A apparently corresponds to a larger
fraction of the IPL in the salamander retina than it does in the cat
retina, where these sublaminas were first defined (on the basis of the
stratification of OFF-center and ON-center ganglion cells) (Nelson et
al., 1978). In other species the division between the two sublaminas is
not so well defined. In the rat retina, for instance, bipolar cells
ramifying in the very center of the IPL may receive OFF-center
excitation via electrical synapses with amacrine cells, but they show
little direct sensitivity to either kainate or APB (Euler et al.,
1996). Also in the turtle retina, where both bipolar cells and ganglion
cells are predominately multistratified, the ON-center-OFF-center
border is not sharply demarcated (Ammermuller and Kolb, 1995). In the
salamander retina, on the other hand, only a very small fraction of
bipolar cells stratify at both distal and proximal levels of the IPL,
and the division between sublaminas A and B is very clear. It is
interesting that those multistratified cells that do ramify in both
sublaminas appear to possess both ON-center and OFF-center synaptic
conductance mechanisms. This suggests a strong developmental link
between the level(s) at which bipolar cell axon terminals stratify in the IPL and the type(s) of glutamate receptors they express at photoreceptor synapses.
Although sEPSCs are clearly associated with photoreceptor inputs to
HBCs, analogous (but sign-inverted) spontaneous synaptic currents are
generally not apparent in DBCs [see Wu and Maple (1998), however].
This probably reflects a difference in the kinetics of the glutamate
receptors on these two types of cells. Photoreceptor synapses on DBCs
use L-AP-4 metabotropic glutamate receptors, which generate
relatively slow conductance changes via a second messenger system
(Slaughter and Miller, 1981; Nawy and Jahr, 1990). Therefore, the
postsynaptic response to transmitter release from a single vesicle, or
cluster of vesicles, at a photoreceptor synapse is likely to be heavily
filtered in DBCs. HBCs, on the other hand, use rapidly activating
ionotropic AMPA receptors (Slaughter and Miller, 1983; Hughes et al.,
1992), which are capable of generating sEPSCs with a rise time of ~1
msec. The difference in the kinetics of these two types of receptors
may be functionally relevant to the processing of visual information in
the IPL. Because HBCs are inherently noisier than DBCs (Ashmore and
Copenhagen, 1980), excitatory input to the IPL is noisier, overall, in
the dark than in bright light (Donner et al., 1990). This trend is
reinforced by a difference in the size of sEPSCs in rod- and
cone-dominated HBCs. The sEPSCs appear to be smaller, on average, in
cone-dominated HBCs, and this also has the effect of making excitatory
inputs to the IPL less noisy under scotopic conditions than under
photopic conditions. Perhaps it is advantageous for the retina to
operate in a more stochastic mode when analyzing dim signals and a less stochastic mode when analyzing bright signals (Ashmore and Falk, 1981).
Large voltage fluctuations in rod-dominated HBCs probably play a
significant role in generating the high frequency of spontaneous action
potentials observed in dark-adapted ganglion cells.
Rod and cone channels
Using spectral difference measurements, we found that the most
rod-dominated DBCs (type 10) ramify very near the proximal margin of
the IPL. A similar stratification has been described for rod bipolar
cells of many other species (Kolb and Famiglietti, 1974; Ammermuller
and Kolb, 1995; Euler et al., 1996). Salamander retinas differ from
mammalian retinas, however, in that they possess rod-dominated HBCs
(Hensley et al., 1993). We have observed that the most rod-dominated
salamander HBCs ramify very near the distal margin of the IPL.
Moreover, for both HBCs and DBCs, the relative strength of rod inputs
tends to decrease as the level of ramification becomes more central in
the IPL. It should be noted that the balance of rod and cone inputs to
bipolar cells may be affected by various experimental conditions,
including the state of light adaptation and the composition of the
Ringer's solution. Under the somewhat light-adapted conditions
described here, the difference between the sensitivities of the most
rod-dominated and most cone-dominated cells is smaller than observed
under strongly dark-adapted conditions (Yang and Wu, 1997). Also, the
absence of bicarbonate in our Ringer's solution may have shifted the
rod and cone balance in favor of the cones (Hare and Owen, 1998),
although this is not clear (Yang and Wu, 1999). Regardless of how such
factors may modulate the rod and cone balance, our data suggest that
cone signals are transmitted predominantly to the central IPL and rod
signals are sent predominantly to the margins of the IPL.
Accompanying these gradients of rod and cone dominance in the IPL are
differences in the kinetics of bipolar cell OFF responses; i.e., the
cone input to bipolar cells moves rapidly toward (and overshoots) its
steady-state dark level, whereas the rod input relaxes more slowly
toward its dark level. Although cones probably contribute to the OFF
overshoots observed in cone-dominated HBCs, the overshoots may also be
mediated by a class of rod (RodC) that is
strongly electrically coupled to cones and exhibits very large transient depolarizing overshoots at light OFF (Wu, 1988; Wu and Yang,
1988). This might explain why sizable OFF tails were observed in the
type 5 HBCs. For these cells the OFF overshoots are so much larger than
ICON that the tail phase of the OFF
response might be dominated by the dynamics of RodC photoreceptors.
Although the OFF responses of cone-dominated DBCs are partially
transient, they never exhibit the large overshoots present in the
responses of cone-dominated HBCs. Again, this probably reflects a
difference between the glutamate receptors of DBCs and HBCs; rapid
transients are heavily filtered by the L-AP-4 receptor
mechanism of DBCs, but not by the AMPA receptor mechanism of HBCs. The
OFF transients of HBCs may be important for motion detection (Miller,
1979), so it is perhaps worth emphasizing that these signals are most
strongly expressed in the proximal portion of sublamina A.
Inhibitory interactions in the IPL
The pharmacology of the inhibitory inputs discussed in this paper
has not been well described, but this inhibition is probably generated
primarily by GABAergic amacrine cell synapses in the IPL (Maple and Wu,
1996, 1998). Most bipolar cells receive chloride-mediated inhibition at
both light onset and offset, and much of this inhibition is probably
generated by ON-OFF amacrine cells, which ramify in both sublamina A
and sublamina B and are excited both at light onset and light offset
(Vallerga, 1981). The size and kinetics of these chloride currents vary
greatly among different bipolar cell types, and numerous circuits are
probably involved in the generation of this inhibition. One possible
circuit is suggested by the fact that a particularly strong and
transient IClOFF was observed for
bipolar cells with ramifications near the very center of the IPL.
Because the cells with the largest excitatory overshoots (the most
cone-dominated HBCs) also ramify near the very center of the IPL, it
seems likely that they provide strong excitatory OFF input to the
amacrine cells that generate this strong, transient IClOFF.
The center/surround nature of these inhibitory inputs has not yet been
investigated, but a few points should be noted concerning receptive
field organization. First, this inhibition cannot mediate surround
antagonism of HBC responses to light onset, because it is synergistic
with the photoreceptor inputs. [ECl
is probably near 60 mV in bipolar cells (Maple and Wu, 1998). This is
negative to the resting potential of bipolar cells in darkness and to
potentials at which bipolar cell synaptic calcium conductances are
measurably activated (Heidelberger and Matthews, 1992).] On the other
hand, OFF inhibition can antagonize the excitatory OFF overshoots
observed in HBCs. In other words, inhibitory inputs from amacrine cells do not contribute to a static inhibitory surround in HBCs, but they
might be important in regulating sensitivity to transient light
stimuli. In contrast, inhibitory inputs from amacrine cells could
contribute to an inhibitory surround in DBCs. This is especially a
possibility for the type 10, rod-dominated DBCs, which exhibit relatively sustained ON inhibition. Bipolar cell inhibitory surrounds are thought to be primarily generated via presynaptic inhibition of
cones by horizontal cells (Werblin, 1977), but in the ON pathway, amacrine cells could conceivably generate an inhibitory surround for
rod signals.
In summary, we have shown an orderly segregation of light response
characteristics (receptive field polarity, balance of rod and cone
inputs, size of EPSCs, and other kinetic parameters) by 12 types of
bipolar cells with axon terminals stratifying at different levels of
the IPL. This segregation simplifies the integration of visual
information in the retina, and it initiates a chain of parallel
processing that is elaborated in higher visual areas of the brain.
| |
FOOTNOTES |
Received Dec. 28, 1999; revised March 27, 2000; accepted April 7, 2000.
This work was supported by National Institutes of Health Grants EY
04446 and EY 02520 and grants from the Retina Research Foundation
(Houston, TX) and the Research to Prevent Blindness, Inc.
Correspondence should be addressed to Dr. Samuel M. Wu, Cullen Eye
Institute, Baylor College of Medicine, 6565 Fannin Street, NC-205,
Houston, TX 77030. E-mail: swu{at}bcm.tmc.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
