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The Journal of Neuroscience, October 1, 1998, 18(19):7836-7846
Glutamate Receptor Activity Is Required for Normal Development of
Tectal Cell Dendrites In Vivo
Indrani
Rajan and
Hollis T.
Cline
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
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ABSTRACT |
Glutamatergic retinotectal inputs mediated principally by NMDA
receptors can be recorded from optic tectal neurons early during their
morphological development in Xenopus tadpoles. As tectal cell dendrites elaborate, retinotectal synaptic responses acquire an
AMPA receptor-mediated synaptic component, in addition to the NMDA
component. Here, we tested whether glutamatergic activity was required
for the elaboration of dendritic arbors in Xenopus optic
tectal neurons. In vivo time-lapse imaging of single
DiI-labeled neurons shows that the NMDA receptor antagonist APV (100 µM) blocked the early development of the tectal cell
dendritic arbor, whereas the AMPA receptor antagonist CNQX (20 µM) or the sodium channel blocker TTX (1 µM) did not. The decreased dendritic development is
attributable to failure to add new branches and extend preexisting branches. These observations indicate that NMDA-type glutamatergic activity promotes the initial development of the dendritic arbor. At
later stages of tectal neuron development when AMPA receptor-mediated synaptic transmission is strong, both APV and CNQX decrease dendritic arbor branch length, consistent with a role for glutamatergic synaptic
transmission in maintaining dendritic arbor structure. These results
indicate that AMPA and NMDA receptors can differentially influence
dendritic growth at different stages of neuronal development, in
correlation with changes in the relative contribution of the receptor
subtype to synaptic transmission.
Key words:
NMDA receptor; dendrite growth; in vivo
imaging; activity-dependent; Xenopus development; retinotectal
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INTRODUCTION |
CNS function depends on the
establishment of precise connections between the presynaptic and
postsynaptic neurons. Activity-independent and activity-dependent
processes operate during the elaboration, pruning, and stabilization of
axonal morphology (Goodman and Shatz, 1993 ; Katz and Shatz, 1996). A
comparable role for activity in the development of dendritic arbor
structure is not yet clear. Several studies indicate that blocking
synaptic activity (Kalb, 1994; Vogel and Prittie, 1995) or sensory
deprivation (Weisel and Hubel, 1963; Feng and Rogowski, 1980;
Constantine-Paton and Ferrari-Eastman, 1981; Lund et al., 1991) during
development can prevent normal elaboration of dendritic arbors. Other
studies show that denervation after synapse formation results in
dendritic atrophy (Valverde, 1968; Benes et al., 1977; Deitch and
Rubel, 1984), supporting a role for afferent activity in maintaining dendritic structure. A third group of studies suggests that dendrites become more elaborate in regions in which afferent inputs have highly
correlated patterns of activity (Katz and Constantine-Paton, 1988; Katz
et al., 1989; Kossel et al., 1995). Other reports come to the opposite
conclusion; blocking NMDA receptors can increase dendritic growth and
spine density (Rocha and Sur, 1995; McAllister et al., 1996). Finally,
several studies conclude that mechanisms controlling dendritic
development are not influenced by synaptic activity (Goodman and Model,
1990; Wong et al., 1991; Dalva et al., 1994; Kossel et al., 1997),
although some of the data do show activity-dependent changes in spine
density (Wong et al., 1991; Dalva et al., 1994; Kossel et al.,
1997).
In the retinotectal projection of Xenopus tadpoles, images
of optic tectal neurons taken over a period of several days in vivo indicate that their morphological development occurs in
distinct stages (Wu and Cline, 1998). Newly differentiated stage 1 neurons undergo axonogenesis, with little elaboration of the dendritic arbor. Over the next 24 hr, neurons enter stage 2, a period of rapid
dendritic arbor growth similar to that seen in zebra fish tectal
neurons (Kaethner and Stuermer, 1997). After 3-4 d of rapid dendritic
growth, neurons enter stage 3, which is characterized by a slower
growth rate and more stable dendritic arbor. The initiation of
dendritic growth correlates with retinotectal synaptogenesis. Glutamatergic retinal inputs mediated principally by NMDA-type glutamate receptors (NMDA R) can be recorded from tectal neurons, with
few dendritic branches (Wu et al., 1996). As the dendritic arbor
elaborates, retinotectal synaptic responses acquire an AMPA receptor
(AMPA R)-mediated component, in addition to the NMDA component. Based
on these observations, we investigated the potential roles of NMDA- and
AMPA-type glutamate receptors in regulating dendritic arbor
elaboration. In particular, we tested whether glutamate receptor
activity is required for the initiation of dendritic arbor development
during the transition from stage 1 to stage 2 and whether the influence
of NMDA and AMPA receptor activity on dendritic morphology changes as
the relative contribution of the AMPA receptors to synaptic
transmission increases. To address this question, we have taken
repeated in vivo images of tectal neurons in the presence
and absence of activity blockers. We find that NMDA R activity is
required for the normal morphological development of young neurons,
although both NMDA R and AMPA R play a role in maintaining arbor
structure in more mature neurons.
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MATERIALS AND METHODS |
Image acquisition. Albino Xenopus
laevis tadpoles were reared as described previously
(O'Rourke et al., 1994). Single neurons at different positions along
the rostrocaudal axis of the tectum of stage 46-48 (Nieuwkoop and
Faber, 1956) tadpoles were labeled by
1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) (0.01% in absolute ethanol; Molecular Probes, Eugene, OR) iontophoresis. Positive current (1-10 nA) was applied in 3-10 pulses
of 200 msec duration. Animals were screened to select those with single
or well isolated brightly labeled neurons. Cells were imaged with a
Noran XL laser scanning confocal attachment mounted on an
upright Nikon Optiphot, using a 40× air lens (0.8 NA; Nikon). Optical
sections were collected at 2 µm steps through the depth of the
neuron. Each optical section was the average of eight frames. Dye
injection, screening, and imaging were done in animals anesthetized with 0.02% 3-aminobenzoic acid ethyl ester (MS222; Sigma, St. Louis,
MO) in Steinberg's rearing solution. Animals recovered from anesthetic
between imaging sessions.
Stock solutions of activity-blocking drugs APV (Sigma), CNQX (Research
Biochemicals, Natick, MA), or TTX (Sigma) were directly added
into the rearing solution to final concentrations of 100 µM DL-APV, 20 µM CNQX, and 1 µM TTX. The first image in all experiments was taken
before the animals were exposed to a drug. Animals were returned to the
rearing solution containing the drug after each imaging session. For 24 hr drug exposure, the rearing solution was replaced with fresh solution
containing the blocker after 12 hr. Animals treated with APV showed
longer bouts of swimming (Witte, 1995). To quantify the length of a
bout of swimming, the behavior was initiated by dropping water into a
Petri dish containing a single animal. The swimming was recorded on
video tape and analyzed later to measure the time spent swimming for
each animal. Analysis was done blind to treatment. CNQX-treated animals
appeared to swim less than controls, but this was not quantified.
Animals treated with 1 µM TTX became immobile after
10-20 min, indicating the penetration of the drug. This concentration
blocks sodium-dependent action potentials in retinal axons and tectal
neurons (Wu et al., 1996). Light-induced increases in calcium in
retinotectal axons are blocked by retinal injections of TTX to yield
similar final concentrations (Edwards and Cline, 1997). Exposure of
animals to 10 µM TTX in the bath killed the animals.
Heart beat and blood flow were monitored throughout the experiment to
ensure viability of the immobilized animals.
Image analysis. Tectal cell reconstruction and morphometric
analysis were performed as described previously for retinal axon arbors
(Witte et al., 1996). Cells were reconstructed by tracing the portion
of the arbor from each optical section onto an acetate sheet until the
entire neuron was drawn. This type of three-dimensional reconstruction
provides a more detailed representation of the morphology than the
computer generated three-dimensional image, because finer processes
visible in the individual optical sections are lost in the
computer-generated reconstructions.
The number of branch tips was counted manually. We use "branch tip"
to designate the terminal branches in the arbor. Branch tips that were
added or retracted over the 4 hr imaging period, as well as the portion
of the dendritic arbor which was stable over the imaging period, were
identified by superimposing the drawings of the cell from the first and
second time points. Total dendritic branch length (TDBL) was measured
from scanned drawings of the cells using NIH Image version 1.61. Growth
rate was calculated as the change in TDBL between two time points
(either 4 or 24 hr), as stated. Because the data were scanned as
two-dimensional drawings and therefore compressed in the Z dimension,
the dendritic branch length measurements underestimate the total branch
length. Neurons imaged in this study were on average 30 µm in total
depth along the z-axis, and this parameter did not differ
between the experimental groups. Neurons accessible for in
vivo imaging are located in dorsal tectum. Because of the shape of
the midbrain, most of the neurons located in this region of the tectum
have their dendritic arbor oriented toward the lateral edge of the brain, parallel to the dorsal surface of the animal. Consequently, loss
of information on the depth of these neurons is minimized compared with
neurons, whose cell bodies are located more laterally in the tectum.
Data are presented as mean ± SE. Statistical significance was estimated using the two-tailed t test, after ensuring
that the data sets satisfied the criteria of the F test for
comparable variances.
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RESULTS |
Relationship between morphological dendritic development and
synaptic maturation
We have reported that glutamatergic retinotectal synaptic
transmission is initially mediated principally by NMDA receptors in
young neurons. As the neurons and synapses mature, the amplitude of the
AMPA component of transmission increases, whereas the amplitude of the
NMDA component remains constant (Wu et al., 1996). We have presented
previously these data as a correlation between the cell body position
along the rostrocaudal axis of the tectum and the AMPA/NMDA ratio.
Here, we have replotted these data to show the relationship between
AMPA/NMDA ratio and TDBL (Fig. 1).
Younger neurons with simple morphologies of TDBL <200 µm have
AMPA/NMDA ratios <1, whereas more mature complex neurons with TDBL
>200 µm have AMPA/NMDA ratios >1. Based on these data, we examined the effects of blocking NMDA and AMPA receptors on dendritic arbor development in simple neurons with TDBL <200 µm and in more complex neurons with TDBL >200 µm.
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Figure 1.
Relationship between dendritic arbor development
and glutamatergic synaptic maturation. Neurons with dendritic branch
lengths <200 µm have AMPA/NMDA ratios <1. Neurons with dendritic
branch lengths >200 µm have AMPA/NMDA ratios >1.
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Glutamate receptor antagonists block dendritic development over
24 hr
To study the effect of glutamate receptor antagonists on initial
dendritic arbor development, confocal images through single DiI-labeled
optic tectal neurons in albino Xenopus laevis tadpoles were collected over 24 hr. Only single well labeled cells with a
rostrally projecting axon and simple dendritic arbors at the first time
point were included in these experiments. Animals were first imaged and
then exposed to either DL-APV (100 µM) or
CNQX (20 µM) in rearing solution for 24 hr, after which a
second image was taken. The drug and the rearing solution were changed
after 12 hr. Control animals were returned to normal rearing solution between imaging sessions.
Continuous exposure to APV for 24 hr significantly retards the growth
rate of the arbor compared with controls (Figs.
2 and 3),
from 260 ± 39 µm/d in control neurons (n = 16)
to 158 ± 18 µm/d in neurons exposed to APV (n = 18; p < 0.05). The growth rate in CNQX-treated neurons
(191 ± 34 µm/day; n = 13) is not significantly
different from controls (p = 0.22). These
observations indicate that NMDA receptor activity is required for the
normal growth of the dendritic arbor in simple neurons.
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Figure 2.
APV slows dendritic arbor growth over 24 hr.
Time-lapse in vivo confocal images of DiI-labeled tectal
neurons imaged at 24 hr intervals. Images in the top row
of each set (0h) were collected at 0 hr, before drug
treatment. Images in the bottom row of each set
(24h) were collected 24 hr after exposure to rearing
solution (CONTROL) or APV, as indicated. Three neurons
from each group are shown in order of increasing dendritic branch tip
numbers at the initial image from left to
right.
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Figure 3.
Quantification of the effect of 24 hr APV and CNQX
exposure on dendritic growth rate. Increase in TDBL over 24 hr in
control, APV-treated, or CNQX-treated neurons. The
number of cells observed (n) under
each condition is shown. *p < 0.05.
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Rapid effects of glutamate receptor antagonists on dendritic
arbor development
The decreased arbor elaboration seen with 24 hr exposure to APV
could be attributable to an increase in branch tip retractions, a
decrease in branch tip additions, an increase in branch length retraction, or a decrease in branch length extension. Each of these
possibilities connotes a different cellular mechanism. To distinguish
these possibilities, we collected images of control and drug-treated
neurons at 4 hr intervals. We chose a 4 hr imaging interval, because
this is a long enough period to see quantifiable increases in TDBL and
branch tip numbers in control neurons but short enough to be able to
follow changes in individual branches with confidence. Animals were
first imaged and then exposed to DL-APV (100 µM), CNQX (20 µM), or TTX (1 µM) in rearing solution for 4 hr, after which a second
image was taken. Control animals were returned to normal rearing
solution between imaging sessions.
Matrix of structural changes
An initial review of the data indicated that a wide range of
morphological changes can occur during development. We therefore found
it useful to first categorize the types of structural changes that
could occur. Figure 4 shows a matrix of
possible ways in which the branch length and branch tip number can vary
independently of each other to produce dendritic arbors with different
morphological features. The prototypical arbor, shown in Figure 4,
top, can maintain a constant value for TDBL and still be
dynamic (1) by compensatory additions and retractions of branches, (2)
by increasing the number of shorter branches so that TDBL does not
change significantly, or (3) by decreasing the number of branch tips
but lengthening the remaining branch(es). These possible changes are
shown in Figure 4, left column. An increase in TDBL does not
necessarily have to result from the addition of new branch tips, as
shown in Figure 4, middle column. Extension of existing
branches or reduction in the number of branches, along with elongation
of the remaining branch(es), can also result in an increase in TDBL. As
shown in Figure 4, right column, TDBL can decrease, whereas branch numbers remain constant by shortening preexisting branches. An
increase in the number of short branches or a decrease in branch tip
numbers can also accompany a decrease in TDBL. Thus, changes in TDBL
can occur independently of changes in branch tip number.
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Figure 4.
Matrix of changes in dendritic arbor morphology as
a function of branch dynamics. A prototypical neuron is shown at the
top. Possible changes in TDBL are shown from
left to right and branch tip number from
top to bottom. Neuronal morphology can
change from the prototype, without any apparent change in branch tip
number or branch length or by increasing or decreasing branch length,
branch tip number, or both.
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Dendritic branch length
Figures 5 and
6 show images and line drawings,
respectively, of neurons imaged at 4 hr intervals under untreated and
experimental conditions. For each condition, four neurons are shown in
order of increasing arbor complexity in Figures 5 and 6,
left to right. In general, control neurons show
significant elaboration of the dendritic arbor, even over 4 hr. The
increase in dendritic arbor structure is a consequence of dynamic
changes in the arbor, including branch additions and retractions, as
well as both elongations and shortening of preexisting branch tips.
Neurons exposed to APV do not show the normal rate of arbor
elaboration.
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Figure 5.
APV blocks dendritic arbor growth over 4 hr
in vivo. Time-lapse in vivo confocal
images of DiI-labeled tectal neurons imaged at 4 hr intervals. Four
cells are shown in order of increasing dendritic branch tip number at
the first image from left to right. The
top row of each set (0h) of images was
collected at the beginning of the experiment before drug treatment. The
bottom row of each set (4h) of images was
collected after 4 hr in rearing solution (CONTROL) or
100 µM APV.
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Figure 6.
NMDA receptor blockade slows dendritic arbor
development in simple neurons. Time-lapse in vivo
confocal images of four DiI-labeled tectal neurons from control animals
or animals exposed to 100 µM APV, 20 µM
CNQX, or 1 µM TTX. Images in the top row
of each set (0h) were collected before drug treatment.
Images in the bottom row of each set (4h)
were collected after 4 hr in rearing solution (CONTROL)
or drug solution, as indicated. Control neurons show increases in
branch length and dynamic changes in the branch tip numbers and
arrangement. Cells from the treated animals show only modest
morphological changes. Growth cones are represented by dotted
outlines.
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To provide a quantitative evaluation of the potential role of activity
on dendritic arbor development, we analyzed the following parameters:
(1) change in growth rate over 4 hr, (2) rates of branch tip additions
and retractions, and (3) branch length additions and retractions. All
groups of cells had comparable branch lengths at the first image (Table
1). Note that tectal neurons do not have
spines.
Control neurons (n = 17) have an initial TDBL of
109 ± 13 µm and a growth rate of 49 ± 15 µm/4 hr (Fig.
7A). APV (n = 24) significantly decreases dendritic growth rate over 4 hr
(p < 0.05), whereas TTX and CNQX do not (Fig.
7, Table 1). To illustrate the range in growth rates within the group
of neurons imaged, we graphed the changes in TDBL for each neuron in
the four treatment conditions over the 4 hr period (Fig.
7B). Control neurons of similar initial arbor sizes can
increase or decrease TDBL or show no detectable change in TDBL over 4 hr. No APV-treated neuron showed the large TDBL increases seen in
control neurons. This suggests that the drug selectively affected
neurons that were in the rapid growth phase of dendritic development.
CNQX- and TTX-treated neurons exhibited a range of growth rates
comparable with control neurons. To test whether the effect of APV on
dendritic growth was reversible, a subset of neurons imaged after 4 hr
exposure to APV were replaced in normal rearing bath and imaged again
the next day. These neurons had a growth rate of 105 ± 20 µm/24
hr (n = 12), indicating recovery of dendritic
growth.
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Figure 7.
Quantification of effect of activity blockade on
dendritic arbor development. A, Growth rate over 4 hr in
control cells and cells from animals exposed to APV, CNQX, or TTX.
Number of cells observed (n) for
each condition in A also applies to C and
D. B, Scatterplots of changes in
dendritic branch length for each neuron under the four conditions. Rate
of branch tip additions (C) and retractions
(D) for control and drug-treated neurons over 4 hr. E, Scatterplots of changes in dendritic branch tip
number for each neuron under the four conditions.
*p < 0.05.
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Branch tip dynamics
The slower dendritic growth rate seen in the presence of APV could
be attributable to an increased rate of branch tip retractions, a
decreased rate of branch tip additions, or both. To address this issue,
we examined rates of branch tip additions and retractions over 4 hr.
Control neurons added an average of 3.9 ± 1.3 branch tips and
retracted an average of 1.2 ± 0.4 branch tips over 4 hr (Fig.
7C,D). APV significantly decreased branch
additions (p < 0.05). Neither TTX nor CNQX
significantly changed branch tip additions or retractions. To
demonstrate the range of changes in branch tip numbers in the groups of
neurons studies, we have graphed changes in branch tip numbers for the
individual neurons under each condition, as shown in Figure
7E. As with changes in TDBL, control neurons are
heterogeneous with respect to changes in branch tip numbers over 4 hr.
This analysis indicates that a decreased rate of branch tip additions
contributes to the decreased elaboration of the dendritic arbor seen
with APV.
Arbor stability
The decreased growth rate seen with APV could also be attributable
to a change in the rates of extension or retraction of preexisting
branches. To determine whether the activity blockers alter the relative
lengths of the arbor that are stable or dynamic over the 4 hr period,
we superimposed drawings (Fig. 8) of the initial and 4 hr images and color coded the dendrites to show stable
portions of the arbor in black, branch length extensions and
branch tip additions in green, and branch length or branch tip retractions in red.
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Figure 8.
Color-coded drawings reveal arbor dynamics.
Composite line drawings were obtained by superimposing the drawings
from the 4 hr time point onto the 0 hr time point. The stable branches
of the arbor are shown in black, branch additions and
extensions in green, and branch retractions in
red. Control neurons show more branch length additions
compared with retractions. APV-treated neurons show fewer additions
than controls.
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The stable portion of the arbor over the 4 hr period (Fig. 8,
black) is comparable for all four groups of neurons (Table
1). APV significantly decreased the dendritic branch extension over 4 hr (Fig. 8, green), from 94 ± 15 µm in controls to
40 ± 6 µm in APV-treated neurons (p < 0.001) (Fig. 9A). APV does not
alter branch length retraction (Figs. 8, red,
9B). CNQX and TTX do not alter arbor stability (Fig. 9).
This analysis indicates that NMDA R activity is required for extension
of branches. Failure to elongate branches in APV contributes to the
decreased growth rate in APV-treated neurons.
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Figure 9.
APV selectively decreases branch extension.
Dendritic branch length increase (A) and decrease
(B) of the arbor for control and drug-treated
neurons. Numbers of cells (n) for
each condition are shown above the bar in
A. *p < 0.001.
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Glutamatergic synaptic activity maintains arbor structure in
complex neurons
To determine whether the robust effect of APV on dendritic
dynamics is specific to the young neurons when the relative
contribution of NMDA R activity to retinotectal synaptic transmission
is high, we tested the effect of APV and CNQX treatment on dendritic
arbor dynamics in more mature tectal neurons with AMPA/NMDA ratios >1. Tectal neurons with TDBL >200 µm (Table
2) were exposed to either APV or CNQX for
4 hr (Fig. 10). Growth rates and
changes in rates of branch tip additions and retractions were compared
with control tectal neurons of similar dendritic arbor complexity. In
contrast to simpler neurons, more complex mature neurons are
significantly affected by exposure to both CNQX and APV.
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Figure 10.
APV and CNQX slow dendritic arbor development in
more complex neurons. Time-lapse in vivo confocal images
of four DiI-labeled tectal neurons from either control animals or
animals exposed to 100 µM APV or 20 µM
CNQX. Images in the top row of each set
(0h) were collected before drug treatment. Images in the
bottom row of each set (4h) were
collected after 4 hr in rearing solution
(Control) or drug solution, as indicated. Control
neurons show modest increases in branch length and branch tip numbers
and arrangement. Cells from APV- and CNQX-treated animals show
decreased morphological changes. Growth cones are represented by
dotted outlines.
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The growth rate of control complex tectal neurons is 34 ± 15 µm/4 hr (Fig. 11, Table 2). APV and
CNQX significantly decrease growth rates in complex neurons over 4 hr
(Fig. 11A). Neither APV nor CNQX significantly
altered rates of branch additions or retractions. These data indicate
that both NMDA R and AMPA R contribute to dendritic arbor growth in
more complex neurons. The net decrease in TDBL in these neurons also
indicates that glutamatergic synaptic activity is required to maintain
dendritic structure.
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Figure 11.
NMDA R and AMPA R maintain dendritic arbor
structure in complex neurons. A, Growth rate over 4 hr
in complex neurons from control animals and those exposed to APV or
CNQX. Numbers of cells observed
(n) for each condition are shown
above the corresponding bars. Growth rates of each APV
and control neuron (B) normalized to its initial
TDBL. Simple cells show relatively greater growth rates than complex
cells. Note that APV-treated neurons with TDBL <200 µm show lower
growth rates than control cells. *p < 0.05.
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Although growth rates for simple and more complex neurons average
46 ± 13 µm/4 hr and 34 ± 15 µm/4 hr, respectively, when growth rates are normalized to the initial TDBL, it is clear that simple neurons have a greater relative growth rate than complex neurons
(66 ± 22 and 10 ± 3%, respectively). Blocking NMDA R has a
greater effect on the growth rate of simple neurons compared with
complex neurons (Fig. 11B). Such an effect is not
seen with CNQX (data not shown).
Summary of tectal cell dynamics
Our data indicate that NMDA and AMPA receptors play different
roles in controlling dendritic arbor structure at different stages of
neuronal development. Early in development when glutamatergic transmission is mediated principally by NMDA R, these receptors are
required for the initial elaboration of the dendritic arbor. Blocking
NMDA R prevents dendritic arbor growth by decreasing new branch
additions and branch extensions. These parameters are unaffected by
blocking AMPA R or voltage-dependent Na+ channels.
At later stages of development when the AMPA R contribution to synaptic
transmission is greater, both AMPA R and NMDA R are required to
maintain normal growth rate and arbor complexity (Fig. 12). The effect of CNQX and APV on more
mature neurons is not attributable to a significant change in branch
tip dynamics but could be attributable to a change in branch length
extension, which is technically difficult to resolve in these
neurons.
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Figure 12.
Summary of effects of activity blockade on
dendritic arbor dynamics in vivo. The glutamate receptor
blockers affect different features of the dynamic dendritic growth at
different stages of neuronal development. A prototypical simple cell
under normal conditions increases in TDBL over 4 hr by adding more
branch length and branch tips than it retracts. APV blocks dendritic
growth by decreasing the rate of branch additions and decreasing branch
extensions. The dendritic arbor of a prototypical complex cell is less
dynamic than that of simple cells. Both APV and CNQX decreased the
dendritic branch length in complex neurons. *** indicates statistically
significant changes;  indicates no significant change.
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DISCUSSION |
Images collected at daily intervals over periods up to 6 d
show the overall pattern of dendritic arbor development in tectal neurons (Wu and Cline, 1998). Here, we imaged optic tectal neurons over
a 4 hr interval to examine the effect of glutamate receptor blockers on
the dynamics of dendritic arbor elaboration at different points during
neuronal development. As neurons develop a more complex dendritic
arbor, predominantly NMDA R-mediated glutamatergic synapses acquire
AMPA R responses. We divided the population of imaged neurons into two
groups, "simple" and "complex", based on electrophysiological
data showing that simple neurons with TDBL <200 µm have an AMPA/NMDA
ratio <1, whereas complex neurons with TDBL >200 µm have an
AMPA/NMDA ratio >1. We exposed neurons to APV and CNQX to test the
relative role of AMPA R and NMDA R in dendritic arbor growth. We find
that dendritic growth in simple neurons is selectively blocked by APV,
supporting a strong role for NMDA R in the initiation of dendritic
arbor development. The data also suggest that NMDA R activity is
specifically linked to mechanisms controlling dendritic arbor growth
and dynamics. Although dendritic growth is more modest in complex
neurons, both AMPA R and NMDA R activity are required to maintain
dendritic growth rate and arbor structure in complex neurons. Thus, the role of synaptic activity on dendritic arbor morphology changes with
development.
Dynamics of dendritic arbor growth under normal conditions
Images of simple neurons collected over a 4 hr interval show an
average net increase in both branch tip number and TDBL, attributable to a relatively greater rate of branch tip additions compared with
retractions and to relatively greater branch length extensions compared
with retractions. We find that neurons that appear morphologically similar at the first image are quite heterogeneous in their growth rates over the 4 hr period. Neurons can show net increases, net decreases, or no net change in branch tip numbers or TDBL over 4 hr. It
is important to point out that neurons that show no changes in these
morphometric parameters over 4 hr can still exhibit considerable branch
dynamics, as documented for the neurons imaged at 30 min intervals over
2 hr (Rajan et al., 1998). For the population of simple neurons we
imaged, growth rate did not correlate with TDBL or the number of branch
tips at the first image (Fig. 7). Nevertheless, simple neurons imaged
over 24 hr do show a net growth of the dendritic arbor. More complex
neurons have a slower growth rate, as shown previously (Wu and Cline,
1998), at least partially attributable to a lower rate of branch
dynamics.
It is possible that the population of tectal cells we have imaged is
heterogeneous. If different tectal cell types have different growth
rates, then this could contribute to the heterogeneity in growth rates
we observed. Multiple tectal cell types have been identified in frogs
according to morphological and electrophysiological criteria (Potter,
1969; Lázár, 1973; Matsumoto and Bando, 1980; Katz and
Constantine-Paton, 1988). However, we have not labeled all these
previously identified cell types in young Xenopus tadpoles. All of the neurons we included in this analysis have a rostrally directed efferent axon. Even so, rostrally projecting neurons may
include several subsets of cell types, which we have not been able to
distinguish based on morphological criteria.
Glutamatergic synaptic activity and dendritic arbor dynamics
Blocking NMDA R early in the period of dendritic arbor
development prevented the initial elaboration of the arbor, whereas blocking AMPA R during this period had no significant effect on arbor
morphology. The differential effects of blocking NMDA R and AMPA R may
reflect the relative preponderance of NMDA R-mediated synaptic
transmission compared with AMPA R-mediated synaptic transmission in
young neurons (Wu et al., 1996), the postulated neurotrophic role for
extrasynaptic NMDA receptors in newly differentiated neurons (Blanton
et al., 1990; LoTurco et al., 1991), as well as the developmentally
regulated change in subunit composition of the NMDA R in developing
neurons (Monyer et al., 1992). NMDA receptor-mediated currents in
neurons from caudal tectum have slower decay kinetics than more mature
neurons (Cline et al., 1997). The prolonged calcium influx via these
receptors could result in significantly greater changes in
intracellular calcium concentration than might result indirectly from
AMPA receptor-mediated depolarization. It is likely that the spatial
and temporal changes in intracellular calcium concentrations directly
regulate the cellular mechanisms controlling cytoskeletal stability and
branch dynamics (Lankford et al., 1996). As neurons mature, their
dendritic structure becomes less dynamic, and their AMPA R-mediated
synaptic transmission increases. Consistent with this shift in
AMPA/NMDA ratio, CNQX has a greater effect on dendritic morphology as
neurons mature.
It is interesting to note that APV can alter branch dynamics and branch
length extensions, whereas TTX has no detectable influence on these
parameters. Such a selective influence of NMDA R activity on neurite
outgrowth has also been reported in cultured Xenopus tectal
neurons (Lin and Constantine-Paton, 1998). These data indicate that
NMDA R activity can influence dendritic arbor development independently
of the generation of sodium-dependent action potentials in tectal
neurons. This could occur by activation of nonsynaptic NMDA R or by
synaptic inputs that are subthresholds for firing sodium-dependent
action potentials. This result also raises the issue of the source of
glutamate to activate NMDA R when afferent activity is blocked by TTX.
One potential source is from spontaneous release of transmitter, which
occurs in the presence of TTX. The relatively high affinity of NMDA R
for glutamate in developing tissue (Kutsewada et al., 1992), as well as
the delayed expression of glutamate transporters during development
(Ullensvang et al., 1997), provide the conditions for low levels of
spontaneously released glutamate to activate NMDA R, even in the
absence of action potential activity.
Because the drugs were added to the rearing solution, the results do
not differentiate between the effects of blocking activity at
retinotectal synapses, intertectal, intratectal, and other connections
or retrograde information because of the tectal axon activity or the
effect of extrasynaptic glutamatergic receptors on dendritic
development.
Significance of arbor dynamics on the functional morphology
One open issue in developmental neuroscience concerns the
reproducible acquisition of morphological type. Based on cell culture work, it seems that different neurons have intrinsic programs to
regulate neuronal structure (Mattson, 1988). The present experiments, as well as previous reports from rodent spinal cord motoneurons (Kalb,
1994) and in chick Purkinje cells (Vogel and Prittie, 1995), indicate
that synaptic activity can shape dendritic structure in
vivo.
Our data support the following model of the control of dendritic
growth. Glutamatergic synaptic activity, one source of which is the
retina, promotes the initial development of the dendritic arbor by
increasing rates of branch tip additions and increasing elongation of
existing branch tips. Once the dendritic arbor has formed, synaptic
activity is required to stabilize and maintain dendritic arbor
structure, consistent with previous studies demonstrating that the loss
of afferent activity leads to dendritic atrophy (Valverde, 1968; Benes
et al., 1977; Deitch and Rubel, 1984). During the phase of rapid
dendritic growth, a local decrease in excitatory input to developing
tectal cell dendrites may reduce local dendritic elaboration, whereas a
local increase in afferent activity may promote local growth. The
decreased branch elongation in APV-treated simple neurons indicates
that synaptic inputs onto major branch tips of the dendritic arbor
stabilize those structures and are required to maintain branch length.
Our data also suggest that synaptic inputs can increase the stability
of the rapidly growing dendritic arbor by decreasing rates of branch
tip retractions in young neurons.
Such a developmental influence of synaptic inputs on dendritic arbor
development may underlie the rostrocaudal bias in the dendritic arbor
of tectal neurons and the preference to arborize in eye-specific
stripes observed in postmetamorphic froglets (Katz and
Constantine-Paton, 1988), as well as in cat cortex (Kossel et al.,
1995), stratification of retinal ganglion cell dendrites (Bodnarenko
and Chalupa, 1993), the selective pruning of dendritic branch tips seen
in cortical layer 5 pyramidal neurons (Koester and O'Leary, 1992), and
oriented dendritic elaboration in barrel cortical neurons (Harris and
Woolsey, 1981). Time-lapse images of dendritic spine dynamics in
hippocampal pyramidal neurons from cultured slices also support a model
in which synaptic inputs stabilize spines during a period of
synaptogenesis (Dailey and Smith, 1996; Ziv and Smith, 1996).
The heterogeneity in rates of dendritic development observed in
untreated simple neurons may reflect differences in the strengths of
synaptic inputs. Perhaps the neurons that appeared relatively stable
over the 4 hr period we have imaged had relatively little correlated
input, whereas other neurons that exhibited considerable growth over
the same period had received highly correlated inputs. This idea is
supported by the observation that the variance of growth rates in
APV-treated simple neurons is relatively small.
We have shown previously that blocking NMDA R disrupts the topographic
organization of the retinotectal axon projection (Cline et al., 1987;
Cline and Constantine-Paton, 1989) and that blocking tectal cell
activity increases arbor dynamics in the presynaptic retinotectal axons
(O'Rourke et al., 1994). These studies and others (Scherer and Udin,
1989; Schmidt, 1990; Schmidt and Buzzard, 1993) suggest a retrograde
effect of retinotectal synaptic activity on axon arbor stabilization.
Consistent with this, a recent report indicates that NMDA R blockade
promotes neurite sprouting and the expression of presynaptic markers in
cultured Xenopus neurons (Lin and Constantine-Paton, 1998).
In contrast, we find that blocking NMDA R decreases rates of branch
additions to the postsynaptic dendritic arbor over the short term and
severely attenuates dendritic arbor growth over 24 hr. These data
suggest that synaptic activity stabilizes presynaptic and postsynaptic
structures but that axons and dendrites respond differently when
activity is blocked.
It is interesting to note that blocking glutamate receptor activity has
a significantly different outcome for more complex neurons compared
with simpler neurons. In complex neurons, blocking glutamate receptors
leads to a net decrease in TDBL, suggesting that synaptic activity is
required not only to promote branch additions and branch length
extensions, as in younger neurons, but also to maintain branches that
are already present at the start of the experiment. This suggests that
synaptic activity can recruit growth-promoting mechanisms in younger
neurons that may not be available for activation in more mature
neurons. These data further indicate that the same pharmacological
manipulation, in this case blocking glutamate receptors, can have a
very different influence on dendritic morphology depending on the
developmental state of the neurons. The different effects of activity
blockers on dendritic development reported in the literature may have
reflected the different developmental stages of neurons when the
experiments were performed, not only with respect to the AMPA/NMDA
ratio but also other cellular elements that jointly control
morphological development.
| |
FOOTNOTES |
Received January 6, 1998; revised July 16, 1998; accepted July 17, 1998.
This work was supported by the Hoffritz Trust, the National Science
Foundation, the National Institutes of Health, and the National Down
Syndrome Society. We thank Kim Bronson and Rukhsana Bari for excellent
technical support.
Correspondence should be addressed to Hollis Cline, 1 Bungtown Road,
Cold Spring Harbor Laboratory, Beckman Building, Cold Spring Harbor, NY
11724.
| |
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Top
Abstract
Introduction
