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The Journal of Neuroscience, May 15, 1998, 18(10):3767-3778
Age-Dependent and Cell Class-Specific Modulation of Retinal
Ganglion Cell Bursting Activity by GABA
Ken F.
Fischer1,
Peter
D.
Lukasiewicz1, 2, and
Rachel O. L.
Wong1
1 Department of Anatomy and Neurobiology and
2 Department of Ophthalmology, Washington University School
of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
Competition for postsynaptic targets during development is thought
to be driven by differences in temporal patterns of neuronal activity.
In the ferret visual system, retinal ganglion cells that are responsive
either to the onset (On) or to the offset (Off) of light exhibit
similar patterns of spontaneous bursting activity early in development
but later develop different bursting rhythms during the period when
their axonal arbors segregate to occupy spatially distinct regions in
the dorsal lateral geniculate nucleus. Here, we demonstrate that
GABAergic transmission plays an important, although not exclusive, role
in regulating the bursting patterns of morphologically identified On
and Off ganglion cells. During the first and second postnatal weeks,
blocking GABAA receptors leads to a decrease in the
bursting activity of all ganglion cells, suggesting that GABA
potentiates activity at the early ages. Subsequently, during the period
of On-Off segregation in the geniculate nucleus, GABA suppresses
ganglion cell bursting activity. In particular, On ganglion cells show
significantly higher bursting rates when GABAergic transmission is
blocked, but the bursting rates of Off ganglion cells are not affected
systematically. Thus, developmental differences in the bursting rates
of On and Off ganglion cells emerge as GABA becomes inhibitory and as
it consistently and more strongly inhibits On compared with Off
ganglion cells. Because in many parts of the CNS GABAergic circuits
appear early in development, our results also implicate a potentially
important and possibly general role for local inhibitory interneurons
in creating distinct temporal patterns of presynaptic activity that are
specific to each developmental period.
Key words:
correlated bursting activity; ferret retina; spontaneous
activity; amacrine cells; retinal development; GABA
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INTRODUCTION |
Connections in the immature nervous
system are often imprecise but become refined into highly ordered
networks by maturity (Constantine-Paton et al., 1990 ; Goodman and
Shatz, 1993; Katz and Shatz, 1996; Nguyen and Lichtman, 1996). Neural
activity not only underlies the fine-tuning of projections from large
populations of cells, but it is also necessary for establishing the
appropriate receptive field properties of individual neurons during
development (Sernagor and Grzywacz, 1996; Weliky and Katz, 1997). It is
thought that information essential for the developmental restructuring of connections is encoded by specific temporal patterns of activity and
that activity alone is insufficient for this process (Hebb, 1949;
Willshaw and von der Malsburg, 1976; Miller et al., 1989; Miller,
1996). This idea is supported by findings in the visual system, in
which the formation of ocular dominance columns and the emergence of
orientation tuning in the primary visual cortex are dependent on
the temporal relationship in the activity patterns of retinal ganglion
cells during development (Stryker and Strickland, 1984; Weliky and
Katz, 1997).
Before vision, the immature retina produces a pattern of correlated
spontaneous rhythmic bursting activity when the connectivity of the
retina with the dorsal lateral geniculate nucleus (dLGN) is being
shaped (Meister et al., 1991; Wong et al., 1993; Feller et al., 1996;
Mooney et al., 1996). Retinal ganglion cells that are responsive either
to the onset (On) or to the offset (Off) of light show an age-related
change in their spontaneous bursting patterns (Wong and Oakley, 1996).
This change coincides with the period when their axonal terminals
segregate to innervate different targets within the dLGN. The bursting
patterns of On and Off ganglion cells are indistinguishable before
On-Off segregation in the dLGN but become distinct as segregation
occurs. The generation of different bursting rhythms in On and Off
ganglion cells results in a pattern of retinal activity that contains
the appropriate cues for driving the activity-dependent remodeling of
their axonal projection patterns (Hahm et al., 1991; Miller, 1996; Wong
and Oakley, 1996; Cramer and Sur, 1997).
How are different patterns of activity generated in the same population
of neurons during development? Because amacrine interneurons are also
active spontaneously (Wong et al., 1995; Feller et al., 1996), we
investigated whether GABAergic amacrine cells that are present by birth
(Karne et al., 1997) play a role in regulating the temporal
characteristics of the activity patterns of the ganglion cells. Using
combined optical recording and intracellular dye-filling methods, we
found that the effects of GABA altered with age; GABAergic inhibition
arose only at the time when On and Off ganglion cell axonal arbors are
segregating in the dLGN. At this time, On compared with Off ganglion
cells exhibited a marked increase in their bursting rates in the
presence of GABAA receptor antagonists. Thus, an "imbalance" in the activity levels of On and Off ganglion cells during the period of On-Off segregation is created primarily by the
emergence of GABAergic inhibition and by a greater inhibition of On
compared with Off ganglion cells.
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MATERIALS AND METHODS |
Timed pregnant ferrets were obtained from Marshall farms (North
Rose, New York). Ferret kits aged between birth (P0) and postnatal day
25 (P25) were used for the imaging studies. The numbers of animals used
were three for P0-P3, nine for P5-P11, eight for P14-P18, and eight
for P20-P24. The eyes were enucleated after the animals were killed
with sodium pentobarbital (>150 mg/ml; Nembutal) or after anesthesia
with 4% halothane (Halocarbon Laboratories, River Edge, NJ), followed
immediately by decapitation. Retinae were removed from neonates in
cold, oxygenated Ames medium (Sigma, St. Louis, MO), buffered to pH 7.4 by sodium HEPES (20 mM; Sigma). The retinae were floated
onto a clean glass slide and mounted scleral side up on a piece of
black Millipore filter paper (HABP; Millipore, Bedford, MA). For
whole-cell recordings, pieces of retinae, ~3 × 3 mm, were
sectioned into 150-µm-thick slices using a fine razor blade mounted
on a chopper with a micrometer-driven stage. For optical recordings,
each retina was halved and mounted on filter paper.
Whole-cell recording. Details of the experimental setup for
whole-cell recording are provided by Lukasiewicz and Roeder (1995). Whole-cell recordings were performed on ferret slices from ages P10 to
P36 (25 cells). Current responses were evoked by puffing GABA focally
in the inner plexiform layer (IPL) using a patch pipette containing 1 mM GABA (in Ames medium) and a Picospritzer (General Valve,
Fairfield, NJ). The pressure was adjusted to give a half-maximal or
smaller response to GABA. GABA receptor antagonists 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide or
gabazine (SR95531; Research Biochemicals, Natick, MA), ( )-bicuculline methobromide, and picrotoxin (Sigma) were applied by locally
superfusing the slice, under computer control. The control bath was
Ames medium. The patch electrode solution consisted of (in
mM): cesium gluconate 106, CsCl 5.8, NaCl 3.4, MgCl2 0.4, EGTA 0.20, and sodium HEPES 10 (all from Sigma).
In some recordings, the patch pipette was filled with an intracellular
solution containing 0.03% Lucifer yellow CH (Sigma). The cells were
voltage-clamped to 0 mV where GABA responses were outward and easily
detected (ECl near 60 mV).
Calcium imaging. The retinae were incubated in an oxygenated
solution containing 10 µM fura-2 AM in 0.001% pluronic
acid (Molecular Probes, Eugene, OR) in Ames medium, pH 7.4. After
incubation for one-half hour at room temperature, the incubation
temperature was raised to 30°C for another one-half hour. The retinae
were then washed in Ames medium and transferred to a
temperature-controlled recording chamber, in which oxygenated Ames
medium was superfused. For retinae older than P11, small slits were
made on the retinal surface using a fine ophthalmic blade, and a
concentrated solution of fura-2 AM [1 µg of fura-2 AM in 1 µl of
DMSO (Sigma) and 5 µl of 2.5% pluronic acid] was dropped over the
slits (see Wong and Oakley, 1996). After 1-2 min, the retinae were
incubated as described above.
The ganglion cell layer (GCL) was viewed using a low light level camera
(SIT, Hamamatsu; Fryer Company, Huntley, IL), and images of the cells
were acquired under computer control (Image 1-FL; Universal Imaging
Corporation, West Chester, PA). Sequential excitation with 340 and 380 nm light was achieved using a shutter and a Lambda-10 filter wheel
(Sutter Instruments, Novato, CA), and each pair of images was acquired
and stored every 1 or 2 sec on an optical disk (Panasonic TQ3038; Fryer
Company). An estimate of intracellular calcium levels
([Ca2+]i) was obtained from a
calibration curve obtained before recording by plotting the ratio of
fluorescence at 340 and 380 nm excitation in the presence of solutions
of low and high calcium concentration (for details, see Wong and
Oakley, 1996).
To assess the effects of the various antagonists, images were collected
before and during superfusion of the solutions containing SR95531,
bicuculline methobromide, picrotoxin, or strychnine (Sigma). A range of
concentrations for each antagonist was applied (25-150 µM for GABAA receptor antagonists and 1-50
µM for strychnine); the results presented here are those
for which the concentrations of antagonist produced a consistent result
at each age and across retinae. Recovery from the drug application was
measured by collecting images after washout of the antagonists. All
solutions were prepared on the day of recording. It was observed that
the baseline value of [Ca2+]i
decreased during the period when bicuculline was in the recording chamber, but no significant decrease occurred with SR95531 or picrotoxin. To examine whether the baseline drop in bicuculline was
caused by a differential absorption of the excitation wavelengths, we
added 100 µM bicuculline to the calibration solutions
(high and low calcium solutions) (see Wong and Oakley, 1996) and
obtained the ratio of the images at 340 and 380 nm excitation. The
ratio was noted to decrease with bicuculline; thus, the differential absorption of UV light by this agent contributes to the effect on the
baseline.
Intracellular dye injections. The details of combining
intracellular dye filling with calcium imaging are given in Wong and Oakley (1996). Briefly, after optical recording, an image of the field
of view was printed on a thermal printer (Sony UP870MD; Fryer Company).
With the guide of this image, an intracellular glass pipette filled
with 1% Lucifer yellow CH (Sigma) and 4% Neurobiotin (Vector
Laboratories, Burlingame, CA) in Tris buffer, pH 8.2, and back-filled
with 0.1 M LiCl2 (Sigma), was guided into the
somata of selected cells. The pipette tip and cells were viewed simultaneously under dim illumination using a Lucifer yellow filter set
(Chroma Tech., Brattleboro, VT). After impalement of the cells, dye was
injected using alternating positive and negative current, 1 nA, at 50 Hz for a few seconds. An image of the dye-filled cell (the dendritic
tree) was then acquired using the SIT camera and stored on optical
disk. Because the dye-filled cells can be easily identified from the
image of the fura-2-labeled somata, we can correlate the bursting
patterns with the morphology of the injected cells.
The dendritic morphologies of the major classes of ganglion cell in the
ferret retina are distinctive and can be recognized by P7 (Wingate et
al., 1992; Wingate and Thompson, 1995). To identify a ganglion cell as
an On- or Off-centered cell, the stratification level of the dendrites
was recorded immediately after dye filling by focusing into the IPL
(see Wong and Oakley, 1996). On-center ganglion cells stratify close to
their somata (within three-fifths of the IPL thickness), whereas
Off-center ganglion cells stratify closer to the inner nuclear layer
(within the outer two-fifths of the IPL) (Nelson et al., 1978). The
thickness of the IPL was determined as the difference between the
depths of the GCL and the inner nuclear layer (INL) within each field
of recording. The dendritic stratification levels were confirmed after
fixation of the tissue with 4% paraformaldehyde in 0.1 M
phosphate buffer, pH 7.4, and after immunoprocessing for Neurobiotin
(see Wong and Oakley, 1996). Because it is not possible to determine
physiologically the receptive field center sign in the ferret ganglion
cells until after the photoreceptor circuits develop in the third
postnatal week (Greiner and Weidman, 1981), the cells classified here
according to their dendritic stratification levels are presumed to be
On- or Off-centered cells.
Cross-correlation analysis. To obtain a quantitative
comparison of the degree of correlated bursting activity between
identified ganglion cells, we converted plots of
[Ca2+]i with time to raster plots as
described in Wong and Oakley (1996). Because the baseline constitutes a
large number of minor fluctuations in
[Ca2+]i, cross-correlating the
raw waveforms of [Ca2+]i with time
leads to spurious correlations that often obscure the correlations of
the peaks (bursts), which are represented by relatively fewer data
points. Using Igor (Wavemetrics), we differentiated the
[Ca2+]i plots to obtain
d[Ca2+]i/dt. By
differentiating the raw calcium traces, the baseline fluctuates around
0.0, and a threshold can be set to filter out the baseline noise. Each
data point that exceeded the threshold was represented by a raster
line. Thus, only [Ca2+]i above the
threshold was represented, and the number of raster lines representing
each burst corresponded approximately to the duration (number of image
frames) of the rise in intracellular calcium during the burst.
Cross-correlation analysis (Spearman correlation matrices) was then
performed on the raster plots using Systat 5.2 (SPSS, Chicago, IL). A
correlation coefficient of 1.0 implies perfect correlation of the
activity of the cell pair, a coefficient of 0.0 implies that the
activity of two cells bear no strict temporal relationship, and a
negative coefficient implies that the bursting of the two cells occur
primarily at separate times. The accuracy in correlating the bursts of
the cells depended primarily on an accurate conversion of the calcium
"bursts" to raster plots. In some cases (although these represented
~2-5% of all recorded bursts), when the changes in
[Ca2+]i are small, some calcium peaks
are lost after setting the threshold. For each cell, the threshold is
chosen as the minimal value for which the bursts observed in the raw
data plot are as accurately represented by the raster plot as possible.
This "error" is minimal in recordings in which the signal-to-noise
is high, and thus the cross-correlation analysis was performed only on
recordings that met this criteria. See Figure 8a for an
example of this procedure.
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RESULTS |
GABA-evoked responses in neonatal ganglion cells
Every cell in the GCL of the neonatal ferret retina showed an
increase in [Ca2+]i in response to
GABA (50-200 µM) during the first 10 d after birth
(three retinae; 180 cells analyzed). Figure
1a demonstrates that cells
that responded to GABA also responded to glycine. By contrast, after
P15, bath application of GABA did not cause a rise in
[Ca2+]i and instead suppressed
spontaneous activity in every cell examined (two retinae; 40 cells
analyzed). An example of this inhibitory effect of GABA on a P18 retina
is shown in Figure 1b.
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Figure 1.
a, Response of a presumed ganglion
cell at P6 to exogenous application of GABA and glycine. The
horizontal bar denotes the duration of drug application.
b, GABA suppression of the bursting activity of a P18
cell in the ganglion cell layer. The duration of GABA application is
marked by the horizontal bar. c-e,
Whole-cell recordings from a P10 ferret ganglion cell. SR95531
(c; 25 µM), bicuculline (d;
100 µM), and picrotoxin (e; 100 µM) reversibly blocked the ganglion cell current evoked
by a puff of GABA (1 mM in pipette; 5 psi; 50 msec) in the
inner plexiform layer. Each current trace is an average
of two to four responses. The short horizontal bar
before the responses indicates the duration of the GABA puff. The cells
were voltage-clamped at 0 mV.
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Previous experiments have suggested that the GABA-evoked response in
mature ferret retinal ganglion cells is mediated primarily by
GABAA receptors, in contrast to that in bipolar cells that is mediated by both GABAA and GABAC receptors
(Lukasiewicz and Wong, 1997). To determine whether GABAA
receptors are primarily responsible for GABA-evoked responses in ferret
ganglion cells at all neonatal ages studied, we monitored responses of
the ganglion cells (25 cells; P10-P36) to puffs of GABA using
whole-cell recording techniques in the presence and absence of the
GABAA receptor antagonists SR95531, bicuculline, and
picrotoxin. Ganglion cells were identified as those cells in the
ganglion cell layer that projected an axon in the nerve fiber layer,
which was apparent after dye-filling with Lucifer yellow from the patch
pipette. For every recorded cell and at every age studied, SR95531
completely abolished the ganglion cell response to puffs of GABA, and
bicuculline and picrotoxin depressed the response by almost the same
extent (Fig. 1c-e, e.g., P10 retina). These results
indicate that GABAA receptors are present on neonatal
ferret retinal ganglion cells and that these receptors are primarily
responsible for GABA-evoked currents in these neurons.
Age-related effects of GABAA receptor antagonists on
ganglion cell bursting activity
Having established that GABAA receptors are functional
and that they mediate the responses of neonatal ganglion cells to GABA, we next examined whether endogenous GABA modulates the spontaneous bursting activity of these cells. We used calcium-imaging techniques to
monitor the effects of SR95531, bicuculline, and picrotoxin on the
burst frequency of cells in the ganglion cell layer at different
postnatal ages. In these recordings, the bursting rhythms were plotted
for cells with relatively large somata (10-25 µm in diameter),
presumed to be ganglion cells, and for cells with smaller somata (4-9
µm in diameter), presumed to be displaced amacrine cells (see
Henderson et al., 1988). Discussed below are recordings from presumed
ganglion cells.
SR95531, bicuculline, and picrotoxin had distinct effects during three
different periods of development. Between P0 and P10, either
spontaneous bursting activity was abolished, or the burst frequencies
were significantly reduced during application of 25-50 µM SR95531 (Fig. 2,
P10). At P15, the effects of SR95531 were more diverse; some
cells continued to burst without a noticeable change in burst
frequency, whereas the bursting rates of other cells were reduced or
abolished (Fig. 2, P15). In contrast, toward the end of the
third postnatal week, SR95531 caused an increase in burst frequency in
many cells, particularly those with relatively low bursting rates in
the control (Ames) solution (Fig. 2, P21). At every age
studied, the effects of bicuculline, picrotoxin, and SR95531 were
similar (compare Figs. 2 and 3). The
effects of these antagonists on burst frequency at the three
developmental periods are summarized quantitatively in Figure
4. To determine the significance of the
effects of each antagonist at each age group, Wilcoxon matched pairs
signed rank tests were performed (Systat 5.2). For P1-P10, SR95531 (25 µM), bicuculline (100 µM), and picrotoxin
(100 µM) suppressed the bursting activity of every cell;
this effect was highly significant for all three antagonists (p < 0.0001). These antagonists caused a
decrease in bursting to a mean level of 3-6% of the baseline bursting
rate, although the extent of suppression varied from cell to cell,
ranging from 0% (complete blockade of activity) to 60% of the
baseline frequency. Between P14 and P16, only 66-86% of all cells
analyzed were suppressed by GABAA receptor antagonists
(p < 0.0001 for all antagonists). These cells
burst at 38-46% of their baseline frequency in the presence of
SR95531, bicuculline, and picrotoxin; the effects were significant
(p < 0.0001). Within the populations of cells the activity of which was not suppressed significantly by the antagonists, SR95531 had no significant effect on the mean bursting rates (p > 0.1; 1 of 10 cells showed an
increase), whereas bicuculline (p < 0.001) and
picrotoxin (p < 0.005) caused a significant
increase in mean burst frequency. However, bicuculline did not evoke an increase in burst frequency in 4 of the 18 cells in this latter population, and the bursting rates in 11 of 24 cells were unaffected by
picrotoxin. When the effects of SR95531 and bicuculline are assessed in
the same cells, both antagonists evoked a similar response (see Fig. 2,
P15), indicating that quantitative differences in the mean
bursting rates of the "unsuppressed" population at P14-P16 may be
because of sampling rather than because SR95531, bicuculline, and
picrotoxin act differently and because the effects of these antagonists
are highly varied at this intermediate stage of development. SR95531,
bicuculline, and picrotoxin produced two distinct effects at P19-P24;
the burst frequency of one population of cells did not change
significantly (p > 0.025), whereas another population showed a highly significant increase in burst frequency (p < 0.001), with a mean increase of 175-225%
of the baseline frequency.
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Figure 2.
Effects of SR95531, a GABAA receptor
antagonist, on the bursting activity of cells in the neonatal ferret
ganglion cell layer. The effects of SR95531 were age-dependent. The
horizontal bars indicate the duration of drug
application. For the P21 recording, recovery from application of
SR95531 was not observed during the short period after drug washout.
Bic, Bicuculline.
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Figure 3.
Effects of bicuculline (Bic) and
picrotoxin (PicTx) on the bursting activity of cells in
the neonatal ferret ganglion cell layer. Bicuculline and picrotoxin
depressed bursting activity in cells in the P6 retina. By contrast, at
P16, bicuculline and picrotoxin suppressed the activity of some, but
not all, cells in the ganglion cell layer. At P22, bicuculline and
picrotoxin caused an increase in bursting activity, seen here also as
an increase in burst amplitude.
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Figure 4.
Quantitative summary of the effects of the
GABAA receptor antagonists SR95531, bicuculline, and
picrotoxin on the burst frequency of cells in the neonatal retinal
ganglion cell layer at three different developmental periods. Burst
frequencies during drug treatment are scored as a percentage of the
baseline (predrug treatment, 100%; dashed lines) burst
frequency. The numbers above each histogram represent
the numbers of retinae and cells (retinae: cells). For the age group
P1-P10, every cell analyzed showed a decrease in bursting rate in
SR95531, bicuculline, and picrotoxin. For the age groups P14-P16 and
P19-P24, each antagonist elicited at least two different responses in
the cells. For each antagonist, the number of cells that
responded either with an increase, a decrease, or no change in bursting
rates is given above each histogram. For example, for
P14-P16, 30 of the 40 cells responded with a decrease in frequency in
the presence of SR95531, whereas the 10 remaining cells showed no
significant change in bursting rates. The significance of the effects
is obtained after performing Wilcoxon matched pairs signed rank tests
on the burst frequencies in the absence and presence of the
antagonists. The asterisks represent a significance of
p < 0.0001; all other significance values are
given above each histogram.
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The results summarized in Figure 4 thus indicate that endogenous GABA
promotes bursting during the first and second postnatal weeks but
progressively acts to suppress bursting activity with maturation. In
addition, although GABA acts uniformly across cells in the ganglion
cell layer in the first and second postnatal weeks, GABA exhibits
diverse effects on the bursting rates of retinal cells after the second
postnatal week.
Effects of glycinergic transmission on bursting activity
Figure 1a demonstrates that neonatal ferret ganglion
cells respond to glycine. To determine whether glycine, like GABA,
plays a role in modulating the bursting activity of retinal neurons at
the various ages, we examined the bursting activity in the presence of
strychnine, a glycine receptor antagonist, and compared this with the
activity in the presence of bicuculline. Recordings were performed
first in either antagonist (strychnine or bicuculline) and then in a
medium containing both antagonists. Figure
5 demonstrates that at P8 and P18,
strychnine (5 µM) alone did not alter the burst frequency
of the cells in the GCL. Changes in bursting activity were detected
only after superfusion with bicuculline. However, we noted that in the
early neonates (before the third postnatal week), bursting activity was
diminished or even abolished at higher concentrations of strychnine
(10-50 µM; n = 10 retinae;
n = 361 cells; data not shown). Conversely, at these
higher concentrations, strychnine caused an increase in the frequency
of bursting by P21 (P21-P24: n = 5 retinae;
n = 149 cells; data not shown). Because the effects of
strychnine may not be specific at the high concentrations (Bähring et al., 1994), it is not possible without the
availability of other glycine receptor antagonists to implicate
conclusively the involvement of glycine in modulating the bursting
activity. The conclusions that can be drawn from strychnine about
glycinergic transmission are further complicated by the finding that
glycine receptors in the retina may be differentially sensitive to this antagonist, although the concentrations of strychnine used in the
current study are well above that necessary to reveal a component that
is less sensitive to this antagonist (Han et al., 1997).
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Figure 5.
Strychnine is ineffective in changing the burst
frequencies of the ganglion cells in P8 and P18 retinae. The burst
frequencies of the cells only changed noticeably when bicuculline
(Bic) was present. Horizontal bars
indicate the duration in which each antagonist was present.
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GABAergic inhibition of putative On and Off ganglion cells
Our current findings show that GABAA receptor
antagonists caused a significant increase in the bursting activity of
many, but not all, cells by P18. This differential effect of blocking GABAA receptors occurs during the period (between the third
and fourth postnatal weeks) in which putative On- and Off-center
ganglion cells develop different burst frequencies (Wong and Oakley,
1996). To examine whether the differential actions of GABA are cell
class specific, we compared the activity patterns of morphologically identified ganglion cells in the presence and absence of bicuculline between the ages of P10 and P24. Putative On and Off ganglion cells
were classified according to their dendritic stratification levels
after intracellular dye-filling with Lucifer yellow (Wong and Oakley,
1996).  -Ganglion rather than  -ganglion cells were selected for a
quantitative assessment of the effects of GABAA receptor
antagonists on On and Off cells, because -cells are more prevalent
in a single field of view (see Wong and Oakley, 1996).
In the older neonates, putative On and Off -ganglion cells were
observed to respond differently to bicuculline application. Figure
6 shows an example of a recording from a
P20 retina. Two dye-filled -ganglion cells are shown; cell 1 (Fig.
6a) is a presumed Off ganglion cell (dendritic
stratification in the outer two-fifths of the IPL; see Materials and
Methods), whereas cell 2 (Fig. 6b) is a presumed On ganglion
cell (dendritic stratification in the inner three-fifths of the IPL).
The bursting rhythms of these cells and four neighboring -ganglion
cells are shown in Figure 6c. In this recording, every On
cell clearly showed an increase in bursting activity in the presence of
bicuculline. In contrast, although the burst frequencies of two Off
ganglion cells increased marginally, another Off cell (top
trace) did not show an apparent increase in bursting rate in
the presence of bicuculline. Addition of strychnine to the
bicuculline-containing medium did not increase the bursting activity
any further (Fig. 6c). Interestingly, even in the presence
of bicuculline and strychnine, the bursts of On and Off cells
consistently occurred in register.
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Figure 6.
Dendritic morphology and bursting patterns of
-ganglion cells in a P20 ferret retina. a,
b, A Lucifer yellow-filled -cell (cell
1) with dendritic processes that stratified in the outer
two-fifths (Off sublamina) of the IPL. b, A neighboring
-cell (cell 2) with dendrites stratifying in the
inner three-fifths (On sublamina) of the IPL. c,
Bursting patterns of cells 1 and 2 and
four other neighboring -cells in the absence and presence of
bicuculline (Bic) and strychnine. Horizontal
bars indicate duration of drug application.
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A quantitative comparison of the burst frequency of On and Off
-cells at different ages in the absence and presence of bicuculline is presented in Figure 7. The burst
frequencies of On and Off -cells from each recorded region of a
retina at the ages indicated are plotted for recordings in Ames medium
(solid circles) or in bicuculline-containing Ames
medium (open circles). As demonstrated previously
(Wong and Oakley, 1996), On and Off -ganglion cells have essentially
the same burst frequency initially (see Fig. 7, P10 cells), but during
the third postnatal week, Off -ganglion cells develop a higher burst
frequency compared with that of the On cells (Wong and Oakley, 1996)
(see Fig. 7). The burst frequencies of On and Off cells diverge more
markedly with age; Off cells adopt a burst frequency between 50 and 200 bursts/hr, whereas the burst frequency of On cells ranged between 10 and 50 bursts/hr (see Fig. 7; compare recordings of On and Off cells in
Ames medium).
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Figure 7.
Burst frequencies of On and Off -ganglion cells
in Ames medium (control, solid circles)
and in the presence of bicuculline (open circles) at
various postnatal ages. For each recorded and dye-filled ganglion cell,
the burst frequency during bicuculline application is plotted directly
above or below the frequency observed in
Ames medium. Putative On and Off cells in the same field of view in
each retina are plotted within the boundary marked by the
vertical ticks on the x axis.
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At P10 (Fig. 7), bicuculline reduced the burst frequency of every
recorded On and Off -cell, corroborating the results shown in Figure
4. At P16 and P17, this unidirectional effect is replaced by a more
ambiguous one; no apparent systematic change in burst frequency can be
detected for either On or Off cells. The effects were not related to
cell class; of the 23 -cells in this age group, 17 cells showed a
decrease in bursting, five cells showed an increase, and the activity
of one cell was not altered (see also Fig. 4). However, between P18 and
P24, the burst frequency of every recorded On -cell was increased in
the presence of bicuculline, with an average increase in frequency of
2.58- ± 0.19 (±SE)-fold. Wilcoxon matched pairs signed rank tests
indicate that the significance of this increase for On cells is
p < 0.0001. In contrast, there was no systematic
increase or decrease in the bursting rates of the population of Off
-cells for the same ages when bicuculline was applied (for the
population of Off cells, the significance level of a change in burst
frequency evoked by bicuculline was p > 0.01). Of the
Off cells that showed an increase in burst frequency, the mean increase
in frequency was 1.27 ± 0.06 fold. Thus, overall, On compared
with Off cells showed a consistent and greater increase in burst
frequency in the absence of GABA inhibition. This implies that On cells
are likely to participate in a larger fraction of bursts (waves) in the
absence of GABAergic transmission. Between P20 and P24 (Fig. 7) in Ames
medium (control), an On cell is active 30 ± 0.06% of the time that an Off cell bursts (n = 5 retinae; n = 53 cells). In the presence of bicuculline,
this percentage increased to 65.6 ± 0.12%. Thus, bicuculline
causes a significant increase in the participation of On cells in the
bursting activity but does not equalize the bursting rates of On and
Off cells.
The increase in bursting rates of On -cells in the absence of
GABAergic interactions suggests that the degree to which the activity
of On and Off cells are correlated increases when GABAergic inhibition
is removed. To examine this in greater detail, we first converted the
raw measurements of [Ca2+]i to raster
plots, which depict the distribution of bursts as vertical
lines, and performed cross-correlation analyses on the rasters (Fig. 8a). The methods
and motivation for generating these rasters are described in Wong and
Oakley (1996) and in Materials and Methods.
View larger version (33K):
[in this window]
[in a new window]
|
Figure 8.
Raw plots of
[Ca2+]i are converted to raster plots
(see Materials and Methods) to perform cross-correlation analysis on
the bursts. a, An example of a recording from a P20
retina that depicts the raw data (top), the differential
plot (bottom), and the corresponding raster plot
(middle). The solid horizontal line in
the differential plot depicts a threshold below which the baseline data
points are "filtered out." Each solid dot in the raw
data trace represents a value obtained within one image
frame. b, Examples of raster plots for -cells in the
presence and absence of bicuculline (Bic) and
strychnine. c, Correlation coefficients between On-On,
Off-Off, and On-Off cells for three P22-P24 retinae in Ames medium
(solid symbols) and in the presence of bicuculline
(open symbols). A coefficient of 1.0 indicates perfect
correlation between the bursts of the cells, and a coefficient of 0.0 indicates that the cells burst independently of each other. The
observation that the coefficients are positive indicates that all cells
(On and Off) burst synchronously when they exhibit a burst (see
Wong and Oakley, 1996). Each symbol represents cells
from the same recorded region of the retina. The change in the
coefficients for each cell pair can be observed by comparing the values
of the solid symbol (e.g., solid
triangle) and the open symbol (open
triangle) plotted immediately above or
below. Note that the coefficient value for every On-Off
pair increased in the presence of bicuculline.
|
|
Figure 8b shows an example of raster plots for two On and
two Off -cells from a P20 retina in the presence and absence of bicuculline and strychnine. Figure 8c shows the Spearman
rank correlation coefficients (Systat 5.2) between the activity
exhibited by pairs of cells from three retinae (P22-P24) in the
presence and absence of bicuculline. A coefficient of 1.0 implies that the bursts of the two cells in a pair are perfectly correlated, whereas
a coefficient of 0.0 indicates that the bursting patterns of the paired
cells share no temporal relationship. The correlation coefficients for
On-On pairs are not systematically affected by bicuculline (Wilcoxon
matched pairs signed rank test; p > 0.1; n = 16 pairs). However, the coefficients for Off-Off
pairs increased significantly in bicuculline (p < 0.005; n = 26 pairs). Bicuculline also caused a
highly significant increase in the correlation coefficients between
On-Off pairs (p < 0.001; n = 52 pairs), with every On-Off pair becoming more correlated in their
activity in the absence of GABAergic transmission via GABAA
receptors.
| |
DISCUSSION |
Changing roles of GABA during development
Our current results suggest that GABA modulates the frequency of
bursting in neonatal ferret ganglion cells during the period when waves
are present (P0-P25). GABAergic modulation of spontaneous bursting
activity has also been detected in the developing turtle retina, in
which bicuculline was found to suppress the bursting activity of
ganglion cells (Sernagor and Grzywacz, 1994). In the neonatal ferret
retina, the sign or direction of the modulatory effects of GABA is
age-dependent. In the early neonate (P0-P11), spontaneous bursting
activity of the ganglion cells is depressed when GABAA
receptors are blocked, suggesting that GABA may be providing an
excitatory drive on ganglion cells at these ages. In contrast, in older
neonates (P18 onward), bursting activity is increased by
GABAA receptor antagonists, implying an inhibitory role for
GABA as the retina matures.
An early occurring "excitatory" effect of GABA on neonatal retinal
ganglion cells has been reported previously in the rat (Bähring
et al., 1994) and in other parts of the nervous system, such as the
hippocampus (Ben-Ari et al., 1994; Leinekugel et al., 1997),
hypothalamus (Chen et al., 1996), neocortex (Yuste and Katz, 1991), and
spinal cord (Rohrbough and Spitzer, 1996). In all these systems,
including the neonatal ferret retina, the excitatory effect of GABA is
mediated by GABAA receptors. This early depolarizing response after activation of GABAA receptors has recently
been shown to result from a high concentration of
Cl in the immature cell (Rohrbough and Spitzer,
1996). In Rohon-Beard spinal neurons of the Xenopus larvae,
a high intracellular Cl concentration is brought
about by an inwardly directed Cl transport
mechanism that sets the GABA reversal potential near 30 mV instead of
60 mV. It is possible that similar transport mechanisms exist in
early neonatal ferret ganglion cells, accounting for the early effects
of GABAA receptor antagonists on the bursting activity.
This transport mechanism may then be modified as ganglion cells mature,
creating decreased intracellular Cl concentrations
under which GABAA receptor antagonists cause an increase in
bursting activity in the older neonates (P18-P25). Future experiments
using perforated-patch recordings will test whether depolarizing or
hyperpolarizing effects of GABA in the developing retina can be
accounted for by developmental changes in this putative transport
mechanism.
Our observation that GABAA receptor antagonists suppress
the spontaneous activity of the early neonatal ganglion cells contrasts with those of Feller et al. (1996), who reported that SR95531 had no
effects on the periodicity of the waves in the early postnatal period
(P0-P10). We believe that our current observations support a role for
GABA in modulating the bursting activity at the early ages (P0-P11).
Because transmitter receptors in immature neurons may not be highly
specific (Bähring et al., 1994), we used different pharmacological agents to block the GABA-evoked currents and elicited consistent changes in the bursting activity. Picrotoxin, which blocks
Cl conductance without binding to the GABA-binding
sites, produced effects on the bursting activity similar to that
observed using the competitive antagonists SR95531 and bicuculline. Our
recordings monitor the responses of individual cells using calcium
indicator dyes, in contrast to recordings of waves in low-power fields
(Feller et al., 1996). But, over the entire field of view in our
recordings, the antagonists affected the bursting activity of every
cell in the early neonates similarly; thus differences in sampling are unlikely to resolve the difference in observations. Feller et al.
(1996) also used whole-cell recordings to monitor the GABA-evoked component of the bursting activity; because the
[Cl]i of the immature ganglion cells
may normally be higher than that set by the pipette solution,
excitatory, inward currents evoked by GABA would become outward in the
whole-cell configuration.
What could be the functional role of a depolarizing influence of GABA
in the early neonates? In the neonatal hippocampus, the depolarizing
effect of GABA is found to reduce the Mg2+ block of
NMDA receptors (Leinekugel et al., 1997). In the immature hippocampus,
this synergistic excitatory effect of GABA and glutamate seems to play
an important role in the generation and synchronization of periodically
occurring giant depolarizing potentials, which are accompanied by
increases in [Ca2+]i (Leinekugel et
al., 1996). In the early neonatal ferret retina, however, NMDA
receptors do not seem to play a major role in the generation of the
bursting activity (Wong et al., 1995). Nevertheless, by raising the
general excitability of the cells, the release of GABA may ensure that
neonatal ganglion cells are more susceptible to depolarization by
another agonist, such as acetylcholine (Feller et al., 1996). Whether
GABA is released tonically or only during a burst remains an issue to
be resolved, although in our whole-cell recordings from the retina of
older neonates (P21-25), bath application of bicuculline and
picrotoxin was observed to cause a steady decrease in the baseline of
the whole-cell current (14 of 18 recorded ganglion cells; data not
shown), suggesting that GABA may be released tonically.
A point to be stressed here is that the effect of GABAergic
transmission is modulatory; acetylcholine release causes spontaneous bursting in the ganglion cells (Feller et al., 1996), and GABA may act
by setting the threshold above which bursting can occur. Furthermore,
our results also demonstrate that GABAergic interactions do not
influence the spread of activity between neighboring ganglion cells;
even when the activity is reduced, the bursts of neighboring cells are
still correlated temporally, and the activity is still likely to spread
as a wave across the retina. As such, mechanisms other than GABAergic
transmission must underlie the spatial spread of spontaneous bursting
activity; these may include synaptic and nonsynaptic interactions
between ganglion and amacrine cells. Several mechanisms, including the
spread of extracellular potassium (Burgi and Grzywacz, 1994a,b),
gap-junctional coupling (Penn et al., 1994), and synaptic interactions
(Feller et al., 1996) have been proposed. The present data, however, do
not distinguish between these possibilities.
Apart from the pronounced effects of GABAA receptor
antagonists on burst frequencies, the antagonists also affect burst
amplitude (the magnitude of the calcium peaks) of the cells. These
amplitude changes may reflect corresponding changes in the spike rate
within the burst. However, simultaneous electrical and optical
recordings are necessary to confirm this relationship before the
effects of burst amplitudes can be analyzed or interpreted.
Age-related modulation of bursting rhythms of On and Off
ganglion cells
Our primary objective in the present study was to determine how On
and Off ganglion cells develop different burst frequencies with age.
Comparison of the bursting patterns of these cells suggests that
GABAergic transmission contributes significantly to the observed differences in On and Off bursting rhythms. The consistent suppression of activity in On compared with Off cells may be achieved in several ways. First, it could be that there is a higher density of GABAergic inputs formed on On compared with Off ganglion cells by P18. Another possibility is that GABAergic inhibition is more strongly developed in
On compared with Off cells, owing to differences in
[Cl]i in these cells during the
second and third postnatal week. Measurements of
ECl for On and Off cells at these ages will
provide more insight into the mechanism underlying the differential
GABA effects.
In the absence of GABAergic transmission, the burst frequency of On
cells, although increased, does not match that of Off cells. Thus,
there are mechanisms, other than GABAergic inhibition, that contribute
to the differences in On and Off bursting rates. One possibility is
that On and Off bipolar cells also contribute to generating the
differences in On and Off ganglion cell bursting activity; the period
when On and Off cells develop distinct bursting rhythms (after the
second postnatal week) coincides with the initial formation of bipolar
ribbon synapses in the IPL (Greiner and Weidman, 1981). As On bipolar
cells are hyperpolarized and Off bipolar cells are depolarized in the
dark (for review, see Wässle and Boycott, 1991), spontaneous
patterns of activity of On and Off ganglion cells may reflect the
activity of their presynaptic bipolar cells. Although glutamate does
not seem to play a prominent role in the waves early in development
(Wong et al., 1995), the possibility that bipolar cells may contribute
to the differences in On and Off ganglion cell rhythms as their
connections mature has not been eliminated. In addition, GABAergic
modulation of the bursting activity could also take place at the level
of the bipolar cell axonal terminals that bear GABAA and
GABAC receptors (Lukasiewicz and Wong, 1997).
How does GABAergic modulation of the retinal bursting activity
affect the competition between On and Off inputs for postsynaptic targets in the geniculate nucleus? The current data indicate that GABAergic inhibition reduces the degree to which the bursts of On and
Off cells are correlated during the period when On and Off sublaminae
emerge in the dLGN. Such a reduction in the correlation strength
between the activity of On and Off cells could lead to the segregation
of their connections at the dLGN (see Lee and Wong, 1996; Miller,
1996). In addition, Off ganglion cells appear to burst more in
synchrony in the absence of GABAergic transmission; GABAergic
inhibition may therefore decrease the competitive advantage that Off
cells might normally have based on their higher mean bursting rates by
reducing their correlation strength (Miller, 1996). Thus, GABAergic
modulation in the retina may help regulate the competitive interactions
that take place in the dLGN by affecting not only the correlations in
the activity between On and Off ganglion cells but also that between
Off and Off ganglion cells.
| |
FOOTNOTES |
Received Nov. 20, 1997; revised Feb. 26, 1998; accepted March 2, 1998.
This work was supported by National Institutes of Health Grant EY10699
and an Esther A. and Joseph Klingenstein fellowship to R.O.L.W., by
National Institutes of Health Grant EY08922 to P.D.L., and by National
Institutes of Health Core Grant EY02687 and a Research to Prevent
Blindness grant to the Department of Ophthalmology, Washington
University. We thank Dennis Oakley for much valued technical support,
Dr. M. Gordon for advice on the statistical analysis, and W. T. Wong, E. D. Miller, and K. Myhr for their helpful comments on this
manuscript.
Correspondence should be addressed to Dr. Rachel Oi Lun Wong,
Department of Anatomy and Neurobiology, Washington University School of
Medicine, 660 South Euclid, St. Louis, MO 63110.
| |
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Top
Abstract
Introduction
