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The Journal of Neurophysiology Vol. 79 No. 1 January 1998, pp. 190-196
Copyright ©1998 by the American Physiological Society
1 Department of Molecular and Cell Biology, Division of Neurobiology, University of California at Berkeley, Berkeley, California 94720; 2 Cullen Eye Institute, Baylor College of Medicine, Houston, Texas 77030; and 3 Moran Eye Center, University of Utah, Salt Lake City, Utah 84132
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Gaal, Lubor, Botond Roska, Serge A. Picaud, Samuel M. Wu, Robert Marc, and Frank S. Werblin. Postsynaptic response kinetics are controlled by a glutamate transporter at cone photoreceptors. J. Neurophysiol. 79: 190-196, 1998. We evaluated the role of the sodium/glutamate transporter at the synaptic terminals of cone photoreceptors in controlling postsynaptic response kinetics. The strategy was to measure the changes in horizontal cell response rate induced by blocking transporter uptake in cones with dihydrokainate (DHK). DHK was chosen as the uptake blocker because, as we show through autoradiographic uptake measurements, DHK specifically blocked uptake in cones without affecting uptake in Mueller cells. Horizontal cells depolarized from about 
70 to 20 mV as the exogenous glutamate concentration was increased from ~1 to 40 µM, so horizontal cells can serve as "glutamate electrodes" during the light response. DHK slowed the rate of hyperpolarization of the horizontal cells in a dose-dependent way, but didn't affect the kinetics of the cone responses. At 300 µM DHK, the rate of the horizontal cell hyperpolarization was slowed to only 17 ± 8.5% (mean ± SD) of control. Translating this to changes in glutamate concentration using the slice dose response curve as calibration in Fig. 2, DHK reduced the rate of removal of glutamate from ~0.12 to 0.031 µM/s. The voltage dependence of uptake rate in the transporter alone was capable of modulating glutamate concentration: we blocked vesicular released glutamate with bathed 20 mM Mg2+ and then added 30 µM glutamate to the bath to reestablish a physiological glutamate concentration level at the synapse and thereby depolarize the horizontal cells. Under these conditions, a light flash elicited a 17-mV hyperpolarization in the horizontal cells. When we substituted kainate, which is not transported, for glutamate, horizontal cells were depolarized but light did not elicit any response, indicating that the transporter alone was responsible for the removal of glutamate under these conditions. This suggests that the transporter was both voltage dependent and robust enough to modulate glutamate concentration. The transporter must be at least as effective as diffusion in removing glutamate from the synapse because there is only a very small light response once the transporter is blocked. The transporter, via its voltage dependence on cone membrane potential, appears to contribute significantly to the control of postsynaptic response kinetics.
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The glutamate concentration at the cone terminal is determined by a dynamic balance among the rates of vesicular release, transporter uptake, and diffusion away from the synapse followed by uptake by retinal Mueller cells (Brew and Attwell 1987 Autoradiography
Isolated tiger salamander retinas were sliced at 40 µm and incubated for 10 min at room temperature in 25-µl droplets of physiological saline containing 2.5 µCi[3H] D-aspartate (~5 µM total D-aspartate) and DHK (0,10, 100, and 1,000 µM), rinsed in cold saline, fixed in mixed aldehydes, epoxy resin embedded, precision sectioned at 500 nm, and processed for light microscope autoradiography (Marc et al. 1978 Electrical recording
Horizontal cells were recorded in the tiger salamander retinal slice (Werblin 1978 Solutions and drugs
Standard amphibian Ringer consisted of (in mM) 112 NaCl, 2.5 KCl, 2 or 0.1 CaCl2 (we used either concentration with similar results), 1 MgC12, 10 glucose, and 5 N-2-hydroxyethylpiperazine-N Selecting cone-driven horizontal cells
We recorded horizontal cell potential in response to full field flashes eliciting maximum responses in light-adapted retinas as a measure of glutamate concentration at the cone synapse. Horizontal cells that were driven primarily by cones, not rods, were selected by eliminating most cells with "tail currents," the slowly decaying hyperpolarizations after the termination of the light stimulus, traditionally associated with rod activity (Attwell and Wilson 1980 Nystatin measurements
Nystatin-perforated patch (Horn and Marty 1988 Autoradiography shows that DHK blocks uptake in cones but not Mueller cells
If one compares the blocking effects of DHK in cones (Eliasof and Werblin 1993
Horizontal cells respond to glutamate concentrations between 1 and 50 µM
We calibrated horizontal cells with different concentrations of bath-applied glutamate as a basis for estimating the relationship between the endogenous glutamate concentration and horizontal cell response. In the slice, potential changes were recorded from horizontal cells in the presence of 500 µM DHK to block uptake and 20 mM Mg2+ to block endogenous glutamate release from rods and cones. Mg2+ reduces the rate of release to levels where quantal events can be measured in both the pre- (Larsson et al. 1996 Voltage range of the calcium activation curve does not overlie the cone response range
Figure 3 shows that the voltage range for the calcium current in cones lies between
DHK slows horizontal cell ON response kinetics
We used the horizontal cell response as a measure of glutamate concentration, taking advantage of the monotonic relationship between concentration and potential as shown in Fig. 2. DHK, added to the bathing solution, depolarized both cones and horizontal cells as shown in Fig. 4. Depolarization in cones was probably due to the block of a transporter-gated chloride current, which has been shown to be outward at
Mg2+ slows horizontal cell OFF kinetics
The results above show that a DHK-induced reduction in the rate of uptake reduced the rate of hyperpolarization at light ON. Here we show that decreasing the rate of release reduced the rate of depolarization at light OFF. Figure 5 shows that addition of Mg2+ to the bath to partially block release caused the horizontal cells to hyperpolarize but had little effect on the cone potential level. The hyperpolarization in the horizontal cells is probably due to the reduction of release from the synapse (Dowling and Ripps 1973
Transporter alone can modulate glutamate concentration at the cone synapse
The DHK effects presented in the earlier section could have been generated by a voltage-independent transporter, slowed by DHK, operating in the presence of voltage-dependent release. To confirm that the transporter itself was voltage dependent like that in Mueller cells (Brew and Attwell 1987
Comparison between transporter uptake at spiking and nonspiking neurons
There is a general understanding that postsynaptic kinetics at most CNS synapses are controlled either by postsynaptic receptor desensitization (Clements et al. 1992 Possible mechanism linking cone membrane potential to glutamate concentration
Our results are consistent with the notion that both the ambient level and the kinetics of glutamate concentration at the cone terminal are controlled by a balance among vesicular release, uptake by transporters, and diffusion. Glutamate concentration is increased via voltage-dependent and voltage-independent vesicular release (Reike and Schwartz 1994) and decreased via diffusion and uptake. Release is probably not voltage dependent over most of the cone response range as shown in Fig. 2, so most of the voltage-dependent control of glutamate concentration is mediated by the transporter working against a voltage-independent release rate (Rieke and Schwartz 1994 Uptake, release, and diffusion are constrained by a diffusion barrier at the cone synapse
These processes of uptake and release appear to operate in a confined extracellular space from which diffusion probably is limited physically by the membranes of cells and glia surrounding the cone terminal (Lasansky 1973 Essential role for the glutamate transporter
The observation that most of the cone response range falls outside the activation range for calcium (Fig. 3) suggests that some other voltage-dependent process may link cone membrane potential to glutamate concentration. Our finding that DHK significantly slows the glutamate removal process (Fig. 4A) suggests that voltage-dependent uptake is at least as rapid as diffusion. If diffusion were predominant, blocking uptake would have had little effect on the rate of removal of glutamate from the synapse. Blocking vesicular release with Mg2+ precludes any possibility of a voltage-dependent process other than the transporter. Our finding that under these conditions light still can cause horizontal cells to hyperpolarize (Fig. 6) suggests that the transporter is robust enough to modulate glutamate concentration. The predominance of the transporter in removing glutamate from the synapse supports the notion that the voltage-dependent glutamate transporter in cones serves as the essential link between cone membrane potential and glutamate concentration.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Sarantis and Attwell 1990). With cone hyperpolarization, glutamate concentration is thought to be reduced by a voltage-dependent decrease in vesicular release (Ayoub et al. 1989; Copenhagen and Jahr 1989), in the presence of diffusion. Paradoxically, most of the calcium activation curve in cones lies at potentials more positive than the light response range (Bader et al. 1982). But the horizontal cells respond over a much larger part of the cone response range where there is little calcium activation. Glutamate also may be released into the synaptic region through a form of voltage-independent release as has been described by Rieke and Schwartz (1994). The misalignment between calcium activation and cone response voltage opens the possibility that glutamate concentration may be controlled through the voltage-dependent glutamate transporter (Eliasof and Werblin 1993; Grant and Dowling 1995; Grant and Werblin 1996; Marc and Lam 1981; Picaud et al. 1995a; Tachibana and Kaneko 1988).
). We monitored changes in the kinetics of glutamate concentration by measuring horizontal cell activity, which we show to be a monotonic function of glutamate concentration. DHK significantly slowed the rate of glutamate removal during cone hyperpolarization, consistent with the notion that uptake contributes significantly to the removal of glutamate.
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
) with 5-day exposures. The radioactive label spread throughout the cone, so it was possible to measure levels of activity corresponding to uptake at sites in the cone far from the synaptic terminal. Images of individual Mueller cells and cones for each DHK dose were captured as 512 × 480 pixel frames (Marc et al. 1990), and the integrated silver grain signal in a standard window measured in all identified cells. D-aspartate was used as a probe for the time-integrated transport because it is metabolically inert and therefore remained within the cell membranes and its activity spread throughout the cells (Fonnum 1984; Marc and Lam 1981).
) with both the current- and voltage-clamp mode of the whole cell patch-clamp technique. Cells were stained with Lucifer yellow and viewed under UV epi-illumination at the end of the experiment to verify cell identity. Horizontal cell isolation was facilitated with papain. Isolated horizontal cells were identified because only their inward rectifying potassium current is blocked with 0.5 mM barium (Dong and Werblin 1996). Electrode resistance fell between 5 and 10 M
.
-2-ethanesulfonic acid (HEPES); pH adjusted to 7.8 with NaOH. Vesicular release was blocked with Mg2+ substituted for Na+, DHK was added without substitution, and 
-aminobutyric acid inputs to photoreceptors and neighboring HCs were blocked with 100 µM picrotoxin. All drugs were bath applied. Intracellular solution consisted of (in mM) 46 KCl, 59 potassium gluconate, 5 CsF, 0.5 MgC12, 0.5 CaC12, 5 HEPES, 1.3 bis-(o-aminophenoxy)-N,N,N,N-tetraacetic acid, 5 Na2ATP, and 0.1 Na3 guanosine 5-triphosphate (Na3GTP) and 0.01% Lucifer yellow and pH adjusted to 7.4 with KOH. EC1 was set to 20 mV (Miller and Dacheux 1983).
).
) was used to eliminate the run-down of the light response and Ca currents in cones. A stock solution of 50 mg/ml (in dimethyl sulfoxide) was diluted to a final concentration of 300 µM/ml in the intracellular solution. A capacitative transient appeared within 5 min after obtaining a gigaohm seal on the cone, indicating access to the cytoplasm, and increased to its final stable magnitude within 20 min.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
; Picaud et al. 1995a) and Muller's cells (Barbour et al. 1991) on the glutamate-elicited current, DHK does not appear to be selective for cones. These results were based on measurements of a combination of transporter and transporter-gated chloride currents. But it has been suggested that the stoichiometric relationship between glutamate transported and the chloride current is not fixed (Billups et al. 1996; Eliasof and Jahr 1996; Fairman et al. 1995), so the earlier estimates of relative uptake may be misleading. To show that DHK is a selective blocker for uptake in cones but not Mueller cells, we measured uptake directly with autoradiography. D-aspartate was used rather than glutamate because L-aspartate is metabolized in Mueller cells, allowing us to measure the radiographic signature for aspartate in both cones and Muller's cells.
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FIG. 1.
Autoradiography of cone and Mueller cell uptake. A: bar graph showing the normalized D-aspartate uptake and the root mean square coefficient of variation for 12-20 cones and Mueller cells at dihydrokainate (DHK) doses of 0, 10, 100, and 1,000 µM. At each concentration, the graph shows the ratio of the mean grain densities for each type. Values of cone uptake in 100 and 1,000 µM DHK differ from Muller cell uptake with P < 0.01. The mean Mueller cell uptake at 1,000 µM DHK was not significantly different from that in the absence of DHK. B: photomicrographs of grain density for normal uptake (left) and for uptake in the presence of 1,000 µM DHK (right). Grains appear throughout the cells, allowing measurement of uptake in regions far from the synaptic terminals where Mueller cells and cone terminals would be difficult to distinguish. C, cones; M, Mueller cells.
).
; Picaud et al. 1995) and postsynaptic (Maple et al. 1994) cells. Horizontal cells depolarized from about 70 to 20 mV over a concentration range from ~1 to 80 µM as shown in Fig. 2A. The data were fit with a logistic function with Hill coefficient of 1.91. This curve may be shifted to the right compared with the true dose-response curve for the glutamate receptors due to the presence of either residual uptake or release in the cone. Either of these conditions would increase the concentration at which the horizontal cells would begin to respond to applied glutamate.
).
, so it is unlikely that Mg2+ would affect horizontal cells.
40 and 0 mV; this is similar to the results of Bader et al. (1982) and Maricq and Korenbrot (1989). However, the majority of the light response lies at more negative potentials, between 40 and 55 mV, although there is a slight slope to this curve even at more negative potentials within the cone response range. Because of this misalignment, it is unlikely that light-elicited, voltage-induced changes in rates of transmitter release, mediated by voltage-dependent changes in calcium entry, could modulate glutamate concentration over most of the voltage range of the cone response. Schwartz (1986) has made a similar suggestion, and Reike and Schwartz (1994) have described a voltage-independent form of vesicular release that could supply glutamate to the synapse over the portion of the response range where voltage-dependent calcium-mediated release is either small or absent. There also might be some increase in calcium current with hyperpolarization due to the increase in driving force on calcium. In the absence of a significant increase in calcium current with depolarization, which would lead to an increase in voltage-dependent release, an additional voltage-dependent mechanism operating over the full cone response range from 40 to 55 mV would be required to link glutamate concentration to cone membrane potential. A likely candidate for this link is the glutamate transporter. The following experiments support the notion that the cone glutamate transporter is involved in controlling glutamate concentration in a voltage-dependent manner.
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FIG. 3.
Comparison of the voltages spanned by the activation curve for Ca2+ and cone light response range. Current-voltage relationship for the calcium current measured in an isolated cone. Calcium begins to activate at about 40 mV and is fully activated near 10 mV. Light response in the same cone lies between 40 and 55 mV. These curves show that there is very little calcium activation over the response range of the cone.
40 mV (Eliasof and Werblin 1993; Picaud et al. 1995b). Cone depolarization then could lead to increase in glutamate concentration, either because voltage-dependent vesicular release was increased or because voltage-dependent uptake was slowed.
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FIG. 4.
Responses in different DHK concentrations at light ON. A: light responses of a cone. Cones depolarized to DHK, but the kinetics of the responses at light ON were only slightly reduced with 300 µM DHK to 98 ± 8% (n = 4) of control. B: responses of a horizontal cell. At 300 µM DHK, the rate of the response onset decreased to 17 ± 8% of control. Results similar to this figure were measured in 10 cells. Kinetics measured as the slope (linear regression) between 10 and 90% of the maximum size of each light response. Each trace is the average of 15 records.
found that DHK depolarized of horizontal cells without any depolarization in cones, suggesting that horizontal cell depolarization was due to partial block of the transporter alone. We cannot distinguish between concentration increases due to a voltage-dependent shift in uptake and release due to cone depolarization or concentration increases due to partial block of the transporter. Because of this ambiguity, we do not use horizontal cell depolarization alone as a measure of DHK block of the glutamate transporter.
) in the presence of an incomplete block of the transporter. Decreases in response kinetics in the presence of transporter blockers have been observed by Yang and Wu (1997) and by Vandenbranden et al. (1996).
; Trifonov 1968). Mg2+ also slowed the horizontal cell OFF kinetics but had no effect on the kinetics of the cone OFF responses. As the Mg2+ concentration was increased, the OFF response rate decreased from ~77 ± 4% of control in 2 mM Mg2+ to 8 ± 4% in 5 mM Mg2+ (n = 6). This decrease in rate of depolarization is consistent with the notion that vesicular release serves to recharge the synapse with glutamate and that the recharging is slower because absolute release rate was decreased in the presence of Mg2+.
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FIG. 5.
Responses in different Mg2+ concentrations at light OFF. A: light responses of a cone. Magnesium hyperpolarized cones but hardly affected the rate of the light response onset (81 ± 11%) and offset (81 ± 6%, n = 6). B: responses of a horizontal cell. At 5 mM Mg2+, the depolarizing response at light OFF, an indication of glutamate increase, was slowed to8 ± 4% control. These records are representative of the measurements in 6 cells. Similar but smaller effects were seen in an additional 7 cells. Kinetics measured as the slope (linear regression) between 10 and 90% of the maximum size of each light response. Voltage scale shown on left, time represented by bar, light where indicated. Cells were recorded separately from different slices.
), we blocked release with 20 mM Mg2+, causing the horizontal cells to hyperpolarize to 70 mV as shown in Fig. 6A. Then 30 µM glutamate was added to the bath, an action that depolarized the horizontal cells to 35 mV. The glutamate concentration at the cone-horizontal cell synapse was probably somewhat <30 µM because of the active uptake of glutamate at the cones and Muller's cells. The calibration curves of Fig. 2A suggest a concentration between 10 and 20 µM for a 35-mV depolarization in the horizontal cells. Under these conditions, a light flash elicited a hyperpolarization in the horizontal cells of 13 ± 7 mV (n = 9) as shown in Fig. 6B. In a separate set of measurements using 20 µM cadmium to block release (not shown here), light elicited a response of 9.7 ± 5 mV (n = 5). The response was slower than normal probably because the transporter uptake was opposed by glutamate diffusion into the synapse, whereas under normal conditions of low external glutamate, diffusion and transport act in the same direction, both moving glutamate out of the synapse. Figure 6B shows that the addition of DHK caused a further depolarization and diminution of the light response, consistent with the results of Fig. 4. This suggests that the light response was generated by the hyperpolarization-induced increase in the uptake rate of the DHK-sensitive transporter alone.
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FIG. 6.
Transporter removes glutamate even in the absence of release. A: normal light response in control conditions and in the presence of 20 mM Mg2+. B: in the presence of 20 mM Mg2+, the addition of 30 µM glutamate depolarized the horizontal cell to 35 mV, and a light flash elicited a 17-mV hyperpolarization to 52 mV. Similar responses were seen in 8 other cells. Further addition of 1 mM DHK depolarized the horizontal cell and blocked most of the light response. C: kainate, which is not transported, elicited no light response. Application of 20 mM Mg2+ hyperpolarized the cell and blocked the light response (bottom). In the presence of 20 mM Mg2+, further addition of 2 µM kainate depolarized the cell to 39 mV but light did not elicit a response (middle, 
). In the presence of 20 mM Mg2+, a light response was recorded in the same cell when 30 µM glutamate was substituted for kainate.
), which would have a depolarizing effect on the horizontal cells.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Hestrin et al. 1990; Takahashi et al. 1995), channel inactivation (Hestrin et al. 1990; Jonas and Spruston 1994; Lester et al. 1990), or diffusion (Clements et al. 1992; Isaacson and Nicholl 1993; Sarantis et al. 1993). These mechanisms can be effective in rapidly terminating the synaptic signal after the arrival of an action potential. Transport appears to play little or no role in controlling postsynaptic kinetics (Hestrin et al. 1990; Isaacson and Nicholl 1993; Sarantis et al. 1993; Tong and Jahr 1994).
). A mechanism is required to modulate glutamate concentration as a function of presynaptic (cone) membrane Potential. Desensitization, inactivation, or diffusion cannot link glutamate concentration to membrane potential. A likely candidate for this role is the glutamate transporter.
). The transporter is both voltage and concentration dependent (Eliasof and Werblin 1993; Picaud et al. 1995). At each steady-state level, the rates of uptake and diffusion are equal and opposite to release. When the cone hyperpolarizes, two changes take place to assure that uptake and diffusion rates remain equal to release: the driving force for uptake increases, causing uptake to increase and glutamate concentration to fall, and as glutamate concentration falls, the net uptake rate is reduced until it is equal once again to release. This mechanism could link membrane potential to glutamate concentration via the transporter.
). The extracellular space also may contain an additional diffusion-limiting matrix as well (Marszalek et al. 1995). The concentration outside the diffusion limited space is maintained at low levels by the transporter at retinal Mueller cells (Barbour et al. 1991; Brew and Attwell 1987). Brew and Attwell (1987) suggest that diffusion from the cone terminal is fast enough to remove glutamate. They may have overestimated the rates of glial uptake because it recently has been shown that part of the uptake current is carried by chloride (Billups et al. 1996; Eliasof and Jahr 1996).
. However, Vandenbranden et al. (1996) suggest that the cone pedicle does not limit the clearance of transmitter form the synapse.
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FOOTNOTES |
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Address for reprint requests: F. S. Werblin, Dept. of Molecular and Cell Biology, Division of Neurobiology, University of California at Berkeley, Berkeley, CA 94720.
Received 26 February 1997; accepted in final form 10 September 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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