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The Journal of Neuroscience, December 1, 2001, 21(23):9151-9159
Distance-Dependent Increase in AMPA Receptor Number in the
Dendrites of Adult Hippocampal CA1 Pyramidal Neurons
Bertalan K.
Andrásfalvy and
Jeffrey C.
Magee
Neuroscience Center, Louisiana State University Health Science
Center, New Orleans, Louisiana 70112
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ABSTRACT |
The Schaffer collateral pathway provides hippocampal CA1 pyramidal
cells with a fairly homogeneous excitatory synaptic input that is
spread out across several hundred micrometers of their apical
dendritic arborizations. A progressive increase in synaptic conductance, with distance from the soma, has been reported to reduce
the location dependence that should result from this arrangement. The
excitatory synaptic contacts within this pathway primarily use AMPA-
and NMDA-type glutamate receptors. To investigate the underlying
mechanism of the increased distal excitatory postsynaptic conductance,
we used outside-out patches and a fast application system to
characterize the properties and distribution of synaptic glutamate
receptors across the range of apical dendrites receiving Schaffer
collateral input. We observed an approximately twofold increase in
AMPA-mediated current amplitude (0.3-0.6 nA) in the range of CA1
apical dendrites that receive a uniform density of Schaffer collateral
input (~100-250 µm from soma). NMDA-mediated current amplitude,
however, remained unchanged. We analyzed the current kinetics, agonist
affinity, single-channel conductance, maximum open probability, and
reversal potential of AMPA receptors and did not find any differences.
Instead, the number of AMPA receptors present in our patches increased
approximately twofold. These data suggest that an increase in the
number of AMPA receptors present at distal synapses may play an
important role in the distance-dependent scaling of Schaffer collateral synapses.
Key words:
CA1 neuron; apical dendrite; AMPA receptor; nonstationary
fluctuation analysis; single-channel conductance; MK-801; extrasynaptic
and synaptic NMDA receptor
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INTRODUCTION |
The elaborately branching dendrites
of hippocampal CA1 pyramidal neurons receive and process information
from thousands of synaptic inputs. One of the simplest ways that
dendrites shape incoming activity is to reduce the amplitude and
increase the width of EPSPs (Rall, 1962 ; Jack and Redman, 1971; Jaffe
and Carnevale, 1999). Because the cable filtering properties of the
dendrites are responsible for this transformation, the effect increases with the distance an EPSP propagates. In this case, the impact of
synaptic input would depend on the dendritic location of the active
synapses, with more distant synapses having a blunted effect when
compared with those located in more proximal regions. It has been
reported recently, however, that unitary EPSP amplitude at the site of
the synapse increases with distance from the soma and that this
increase helps counterbalance some of the filtering effects of the
dendrites (Stricker et al., 1996; Magee and Cook, 2000). The final
result is that, for Schaffer collateral input to CA1 pyramidal cells,
unitary EPSP amplitude at the soma does not show a marked dependence on
the dendritic location of the activated synapse.
A progressive increase in unitary synaptic conductance appears to be
primarily responsible for the increase in dendritic EPSP amplitude
observed in CA1 pyramidal neurons (Stricker et al., 1996; Magee and
Cook, 2000). Several other studies, in the hippocampus as well as in
other CNS regions, have also reported synaptic efficacy to be
relatively location independent. These studies further suggest that an
increase in synaptic conductance is the primary mechanism (Inasek and
Redman, 1973; Korn et al., 1993; Stricker et al., 1996; Alvarez et al.,
1997). Finally, the distal apical dendrites of both neocortical and
hippocampal pyramidal neurons have been found to be more sensitive to
glutamate than the proximal dendrites (Pettit and Augustine, 2000;
Frick et al., 2001).
To further investigate potential postsynaptic mechanisms underlying the
increased synaptic conductance of distal synapses, we directly recorded
from the site of input using outside-out patches made from dendritic
regions receiving Schaffer collateral synaptic input. Rapid application
of glutamate to excised patches was used to estimate various
postsynaptic properties, including AMPA receptor (AMPAR)
numbers, affinity, single-channel conductance, maximum open
probability, channel kinetics, and current-voltage (I-V) relationships in hippocampal CA1 pyramidal
neurons. Although we found no evidence of any location dependence of
AMPA receptor subunit composition or channel modulation, we did observe
a greater than twofold increase in AMPA receptor numbers. The data
suggest that distal synapses contain a larger number of postsynaptic
AMPA receptors compared with proximal synapses and that this elevation in receptor number could participate in generating the
distance-dependent increase in unitary synaptic conductance found in
these cells.
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MATERIALS AND METHODS |
Preparation and visualization of hippocampal slice.
Hippocampal slices (400 µm) were prepared from 6- to 12-week-old
Sprague Dawley rats using previously described standard procedures
(Magee, 1998). Experiments were conducted using an upright Ziess
(Oberkochen, Germany) Axioscope fit with differential
interference contrast optics using infrared illumination. Patch
pipettes (5-11 M ) were pulled from borosilicate glass (EN-1; Garner
Glass, Claremont, CA) and filled with an internal solution containing
(in mM): 140 KMeSO4, 1 BAPTA, 10 HEPES, 4 NaCl, 0.28 CaCl2, 4.0 Mg2ATP, 0.3 Tris2GTP, and
14 phosphocreatine, pH 7.3 with KOH. Currents were recorded in
voltage-clamp mode using an Axopatch 200B amplifier (Axon Instruments,
Foster City, CA), filtered at 2 kHz and digitized at 20 kHz
using Igor Pro XOPs (WaveMetrics Inc., Lake Oswego, OR). The normal
bath external solution contained 125 mM NaCl, 2.5 KCl, 1.25 mM
NaH2PO4, 25 mM NaHCO3, 2 mM CaCl2, 1 mM MgCl2, and 25 mM dextrose, bubbled with 95%
O2 and 5% CO2 at room
temperature, pH 7.4. All neurons had resting potentials between  60
and 75 mV.
Formation and size estimation of dendritic patches.
Outside-out patches were excised from apical dendrites to apical tufts (0-300 µm). Pipettes with a resistance of 5-11 M had an
estimated diameter tip of ~1.5-2 µm. Sodium channel density is
relatively uniform along the dendrite (Magee and Johnston, 1995;
Colbert and Johnston, 1996). Thus, to examine whether the surface area of patches excised at different locations along the dendrite were the
same, peak Na+ current amplitudes were
examined. Outside-out patches were held at 80 mV, and membrane
voltage was stepped to 20 mV for 100 msec. Consistent with previous
findings, sodium channel densities were independent of patch location
(soma, 16.07 ± 3.03 pA; 125 µm, 20.27 ± 4.85 pA; 250 µm, 17.5 ± 5.05 pA), indicating that patch size was
approximately uniform.
Fast application. Fast application of agonist was performed
as described previously (Colquhoun et al., 1992). Briefly,
double-barreled application pipettes were fabricated from theta glass
tubing, and solutions were perfused through control and agonist barrels at a rate of ~0.3 ml/min by means of a multilined peristaltic pump.
The puffer external solution contained (in mM):
125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 10 HEPES, 2.5 CaCl2, and 50 dextrose, pH 7.4. The 20-80%
exchange times varied between 100 and 200 µsec. Outside-out patches
were placed in front of the control barrel. Movement of the application
pipette, by means of a piezoelectric element, was used to apply agonist
to the patch membrane. After each patch recording, the application
system was tested by breaking the patch and measuring the open tip
current caused by a jump from a 10 to a 100% puffer external solution.
In addition, puffer solutions containing different concentrations of
agonist and/or antagonist were exchanged using solenoid valves.
Estimation of synaptic versus extrasynaptic portion by electric
stimulation. Afferent axons were stimulated by a tungsten bipolar
electrode (A-M Systems, Carlsborg, WA), located within 10-25 µm of
the dendrite. Trains of three to five consecutive pulses at a frequency
of 100 Hz were applied every 20 sec for 10 min to stimulate glutamate
release from adjacent nerve terminals. Synaptic stimulation was large
enough to evoke several action potentials during the train. These
experiments were performed at 34-35°C to decrease glutamate
spillover. In addition, the CA3 region of the hippocampus was removed
to avoid spontaneous glutamate release, and 10 µM bicuculline methiodide was added to the
external bath solution. Furthermore, the bath external solution
contained 1 mM Mg2+
to reduce spontaneous NMDA channel openings. Application of 20 µM (5R,
10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]
cyclohepten-5,10- imine/dizocilpine (MK-801) (Research
Biochemicals, Natick, MA) to the bath external solution was used to
block NMDA receptors that were gated by the stimulated synaptic
activity. In addition, the effects of MK-801 were tested without
electrical stimulation in the presence of 0.5 µM external TTX (Research Biochemicals). To
determine the amount of NMDA channel block, outside-out patches were
excised from the stimulated region of the apical dendrite 10 min after
MK-801 washout.
Data acquisition and analysis. Acquiring, analysis, and
fitting of data were performed using interactive programs (Igor Pro). AMPA current activation and deactivation were fit by single-exponential function, whereas desensitization was best fit by double-exponential function. The rise times were determined as the time during which the
current rises from 20 to 80% of the peak value. Patches showing rise
times >1 msec were assumed to have an improper patch configuration and
were removed from analysis.
The concentration-dependent relationship for AMPA-activated peak
current was determined using increasing concentrations of glutamate (10 µM to 10 mM) applied by 100 msec application
pulse. Concentration-response data were fitted by the Hill equation: effect = effectmax/[1 + (EC50/c)n],
where c is the agonist concentration, n is the
Hill coefficient, and EC50 is the concentration
at which the half-maximal response was obtained.
Microscopic properties of AMPA channels were examined using
nonstationary fluctuation analysis (Sigworth, 1980). AMPA currents were
evoked every 2-3 sec by a 1 msec pulse of 10 mM glutamate in the presence of 1 mM Mg2+.
Between 20 and 100 traces per patch were obtained for analysis. The
mean variance ( 2), determined from all
responses, was plotted against the mean current for all responses. The
plot was fitted with the following function:
2 = iI (1/N)I2 + b2, where I
is the total current, i is the single-channel current, N is the number of available channels in the patch, and
b2 is the variance of
the background noise.
Single-channel conductance ( ) was determined as the chord
conductance: = I(Vh Vrev), where
Vh is the holding potential, and
Vrev is assumed to be 0 mV.
The open probability (Po) is
determined by the following equation:
Po = I/(i/N).
Numeric values are given as means ± SEM. Error bars
in the figures indicate SE and are plotted only if they exceed the size of the symbol. Statistical significance was examined using
Student's t test at the 5% level of confidence.
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RESULTS |
AMPA current amplitude versus distance
Outside-out patches were excised (Jonas and Sakmann, 1992;
Spruston et al., 1995) from the apical dendrites of CA1 pyramidal neurons at various locations in stratum radiatum, ranging from stratum
pyramidale to the border of the perforant path in the stratum lacunosum
moleculare (S.L.M.). Dendrites within this region form spiny
glutamatergic synapses with the axons of CA3 pyramidal neurons
comprising the Schaffer collateral pathway. Patches were voltage
clamped at 80 mV, and AMPA currents were activated by 1 msec pulses
of 1 mM glutamate using a rapid glutamate application system (Clements et al., 1992).
The peak amplitude of the AMPA current increased approximately
threefold for patches excised from the soma compared with patches excised from distal regions [soma, 192 ± 52 (n = 6); dendrite ~250 µm, 566 ± 74 pA (n = 14);
p < 0.005]. Anatomical studies have shown that there
are few spines, and therefore Schaffer collateral synapses, formed on
the proximal portion of rodent hippocampal CA1 pyramidal neurons (soma
to just <100 µm distal) (Andersen et al., 1980; Bannister and
Larkman, 1995; Trommald et al., 1995). At this point (~100 µm),
spine density reaches a constant value in rodent hippocampal slices
that is maintained over the entire span of the Schaffer collateral
input to the apical dendrites (~1.0
spines/µm2) (Andersen et al., 1980;
Bannister and Larkman, 1995; Trommald et al., 1995).
Therefore, much of the initial increase in AMPA current from the soma
to 100 µm distant can be the result of the increase in synapse
density (Andersen et al., 1980; Bannister and Larkman, 1995; Trommald
et al., 1995). The remaining approximately twofold increase in
dendritic AMPA current amplitude, however, occurs across dendritic
regions that have a constant spine density [from 276 ± 42 pA at
100 µm (n = 11) to 566 ± 74 pA at 250 µm
distal (n = 14); p < 0.005] (Fig.
1A). The slight
decrease in AMPA current observed in the most distal patches (300 µm)
is likely the result of these patches being in or near S.L.M in which
spine density has been observed to again decrease (0.60 ± 0.17 spines/µm2).
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Figure 1.
AMPA receptor-mediated glutamate currents in
excised patches from different dendritic locations. A,
Currents activated by 1 msec application of 1 mM glutamate
to outside-out patches excised from either a proximal (~50 µm from
soma) or distal (~250 µm from soma) dendritic location. Currents
were recorded in the presence of 1 mM
Mg2+ and in the absence of glycine. Each
trace is an average of five sweeps
(Vh was 80 mV). B, AMPA
receptor-mediated mean current amplitudes are plotted against the
location of the excised patches from the soma (n = 69). Current amplitude increases approximately threefold across the
range. Open circles are the peaks of single patches, and
filled circles are the means of these patches with SE
bars.
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The variability of AMPA current amplitude between patches could be the
result of several factors, including patch area, the number of synapses
per patch, and the number of receptors per synapse. The smallest AMPA
current amplitudes appear to be uniform across the dendritic axis, and
this is reminiscent of the previous observation that the
smallest-amplitude EPSCs are also independent of distance from the
soma. These data suggest that only a subset of all synapses may be
scaled with distance.
In summary, we observed an approximately twofold increase in AMPA
receptor current across the range of CA1 apical dendrite that receives
a uniform density of Schaffer collateral input (Fig. 1B). In general terms, the increase in current
amplitude could be the result of differences in the number of channels
present in our patches or to differences in the properties of these
channels. The experiments described below were designed to distinguish
between these two possibilities.
Agonist affinity
To determine whether receptor glutamate affinity increased with
distance from the soma, we examined dose-response relationships for
AMPA-activated current from proximal and distal locations. Increasing
concentrations of glutamate (10 µM to 10 mM,
100 msec pulse) were applied to patches excised from 50 and 250 µm
distal from soma. All peak current values were normalized to the peak responses (10 mM glutamate) and then plotted against
concentration (Fig.
2A). After being fit by
a binding isotherm, dose-response curves did not show any significant
shifts, with the EC50 of the proximal patches
being equal to that of distal patches [436 µM (n = 6) and 479 µM
(n = 7), respectively]. These data suggest that the
agonist affinity of AMPA receptor is uniform with distance from the
soma in CA1 pyramidal neurons.
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Figure 2.
Agonist affinity and voltage dependence of AMPA
receptor-mediated glutamate current. A, Mean amplitude
of AMPAR currents evoked by fast application of
10-104 µM glutamate with 100 msec
pulses to proximal patches (~50 µm from soma; n = 6; dashed line with filled triangles)
and distal patches (~250 µm from soma; n = 7;
solid line with open circles). Currents
were normalized to the response at 10 mM glutamate.
B, C, AMPA currents evoked by the
application of 1 mM glutamate for 1 msec
(Vh was 80 to +80 mV, 20 mV steps) to
proximal (B) and distal (C)
excised patches. Each trace is a single sweep.
D, Mean amplitude of AMPA currents for different holding
potentials (Vh was 80 to +80 mV, 20 mV
steps) during fast application of 1 mM glutamate for 1 msec
to proximal (~50 µm from soma; n = 5;
dashed line with filled triangles) and
distal (~250 µm from soma; n = 6; solid
line with open circles) patches. Currents were
normalized to the response at 80 mV. In most cases, the size of the
symbols are bigger than the SE bars. In all experiments,
0.1-1 mM Mg2+ was added, with no
additional glycine.
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Current-voltage relationship
Differences in rectification or reversal potential can suggest
possible AMPA receptor subunit composition change (Mosbacher et al.,
1994). We determined the I-V relationship of dendritic AMPA
channels from outside-out patches excised at various locations along
the dendrite. Patches were held at 80 mV, and membrane voltage was
stepped up to +80 mV in 20 mV increments (Fig.
2B,C). Peak currents were measured
and normalized to the maximum current recorded at 80 mV. Proximal (50 µm) and distal (250 µm) AMPA currents displayed a linear
I-V relationship and had reversal potentials of 4.2 ± 1.82 mV (n = 4) and 4.4 ± 1.45 mV
(n = 6), respectively (Fig. 2D). The
slope conductance (Gm) of the
proximally excised patches was 2.56 ± 0.44 nS compared with
7.96 ± 1.68 nS for distal patches.
Kinetics
Because the kinetic properties of AMPA receptor-mediated current
are important for shaping glutamatergic EPSCs, we examined the location
dependence of AMPAR kinetics. The kinetic properties of the AMPA
currents were studied using glutamate pulses ranging in duration from 1 to 100 msec. For all durations, the currents rose rapidly to a peak and
decayed within 10-20 msec, producing identical peak currents. The rise
time of the current evoked by a 1 msec pulse of 1 mM
glutamate could be fit by a single rising exponential, with a time
constant of 0.58 ± 0.02 msec and a 20-80% rise time of
0.47 ± 0.01 msec, across the dendrites (n = 69)
(Fig. 3A). The current
deactivation could be fit by a single exponential, with a time constant
of 2.8 ± 0.1 msec (Fig. 3B) with no location-dependent differences observed across the somatodendritic axis. During 100 msec,
1 mM glutamate pulses, the current decayed with a
double-exponential time course having time constants of 7.6 ± 0.30 msec ( 1, fast component, 90.3 ± 0.84%) (Fig. 3C) and 25.69 ± 1.38 msec
(2, slow component, 9.7 ± 0.84%) (Fig.
3D). There were no location-dependent differences in the
desensitization kinetics or in ratio of fast and slow component
observed (p > 0.05) (Fig. 3E).
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Figure 3.
Kinetic properties of AMPAR-mediated glutamate
currents versus location. A, Mean of 20-80% rise time
of AMPA current evoked by 1 msec application of 1 mM
glutamate on outside-out membrane patches excised from various
locations of apical dendrites. B, Mean of deactivation
time constants () of the same AMPA currents evoked as in
A. C, Mean of fast desensitization time
constants (1) of AMPA currents evoked by 100 msec
application of 1 mM glutamate to outside-out patches taken
from various locations of apical dendrites. D, Mean of
slow desensitization time constants (2) of the
same currents as in C. E, Mean of the
desensitization time constant ratio of AMPA currents shown in
B and C. In all experiments, 0.1-1
mM Mg2+ was added with no additional
glycine. In each figure, error bars represent the SEM
(n = 69).
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Concentration dependence of rise time and desensitization
time course
The rise time and desensitization of glutamate-activated AMPA
current decreased in a concentration-dependent manner. The 20-80% rise time decreased with increasing glutamate concentration (1 msec
pulses of 100 µM to 10 mM) from 1.9 ± 0.1 to 0.2 ± 0.01 msec on patches excised from 50 µm from soma
(n = 6). The same decrease was seen from 2.1 ± 0.2 msec with 100 µM to 0.2 ± 0.04 msec
with 10 mM glutamate on patches excised from 250 µm (n = 6) (Fig.
4A). The decay phase of
the current (evoked by 100 msec pulses of 100 µM to 10 mM glutamate)
traces was fit with the sum of two exponential functions. The
predominant fast component (1) showed a
concentration-dependent decrease from 9.7 ± 1.5 msec with 100 µM glutamate to 6.6 ± 0.7 msec
(n = 12) with 10 mM glutamate. No
difference was found in values between proximally (n = 6) or distally (n = 6) excised patches. The fast
desensitization time constant was plotted against glutamate
concentration from both locations together (Fig.
4B).
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Figure 4.
Concentration dependence of AMPA current rise and
desensitization. A, Concentration dependence of AMPA
current 20-80% rise time for a 100 msec application of various
concentrations of glutamate (100-104
µM). Data from proximal (~50 µm from soma;
n = 6; dashed line with
filled triangles) and distal (~250 µm from soma;
n = 6; solid line with open
circles) patches are shown. Glutamate concentration is shown in
log scale. B, Concentration dependence of the fast
desensitization time constant (1) with 100 msec
application of glutamate for proximal (~50 µm from soma;
n = 6; dashed line with
filled triangles) and distal (~250 µm from soma;
n = 6; solid line with open
circles) patches. Glutamate concentration is shown in log
scale.
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Nonstationary fluctuation analysis
We next examined several single-channel properties of dendritic
AMPA receptors, namely the single-channel conductance and maximum open
probability (Po,max), to determine
whether there were any location-dependent differences. The
single-channel conductance of AMPA channels () was estimated using
nonstationary fluctuation analysis of current evoked by 1 msec pulses
of 10 mM glutamate (Sigworth, 1980). Between 20 and 100 traces per patches were obtained for analysis. The mean
variance (2), determined from all
responses, was plotted against the mean current for all responses (Fig.
5A,B).
The plot was fit by a parabola (see Materials and Methods) to yield
estimates of and the number of available channels
(N). Data from 125 µm from the soma
(n = 4) and 250 µm from soma (n = 5)
resulted in similar values for of 9.83 ± 0.69 and 9.42 ± 0.95 pS, respectively (Fig. 5C). The probability of any
given channel being open at the peak of the response
(Po,max) was also similar in both
locations: 0.83 ± 0.01 and 0.84 ± 0.02, respectively (Fig.
5C). An approximately twofold increase in channel number was
detected between the groups (N = 467 ± 42, proximal 125 µm from soma; N = 1041 ± 206, distal 250 µm from soma; p < 0.05) (Fig.
5D). These data, together with that described above,
strongly suggest that the observed increase in AMPA current amplitude
is the result of an increase in the number of channels present in the
patch and not to any alteration in AMPA receptor properties.
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Figure 5.
Nonstationary fluctuation analysis of
AMPA receptor-mediated glutamate current. Mean variance plotted as a
function of the mean current for a proximal (A)
and distal (B) patch. Solid line
is fit of the data by a parabolic equation (see Materials and Methods)
that was used to determine single-channel conductance (),
channel number (N), and maximum open probability
(Po,max). Proximal patch from ~125
µm from soma and distal patch ~250 µm from soma.
C, Single-channel conductance (left axis,
filled circles) and maximum open probability
(right axis, open circles) versus
location of the patches. Currents were evoked by a 1 msec application
of 10 mM glutamate with 1 mM
Mg2+ and in the absence of glycine.
D, AMPA receptor number (N) versus
patch location determined from the same patches as in C.
Open circles are the N of single patches;
filled circles are the mean of these patches with SE
bars.
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NMDA current amplitude versus distance
NMDA currents were activated on excised patches by 10 msec pulses
of 1 mM glutamate in the presence of 10 µM
glycine with 5 µM CNQX or 1 µM
2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[F]quinoxaline. The peak
amplitude of NMDA current does not change significantly with distance
from the soma (Fig.
6A), because NMDA
currents from patches excised from the soma and distal dendrites (250 µm) had peak current amplitudes of 71.63 ± 19.35 pA
(n = 6) and 52.33 ± 10.19 pA (n = 10; p > 0.05), respectively. Furthermore, dendritic NMDA currents do not change in patches excised at regions between 100 and 250 µm distal to the soma [54.34 ± 10.97 pA
(n = 6); 52.33 ± 10.19 pA (n = 10); p > 0.05] (Fig. 6B).
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Figure 6.
NMDA receptor-mediated glutamate currents in
patches excised from different distances from soma. NMDA
receptor-mediated currents activated by a 10 msec pulse of 1 mM glutamate to either proximal (A)
(~50 µm from soma) or distal (B) (~250 µm
from soma) patches show the same amplitudes. Currents were recorded in
the presence of 10 µM glycine and in the absence of
Mg2+. Each trace is an average of
five sweeps (Vh was 80 mV).
C, NMDA receptor-mediated mean current amplitudes are
plotted against the location of the excised patches from soma on apical
dendrite (n = 60). Open circles are
the peaks of single patches; filled circles are the
means of these patches with SE bars.
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Kinetics
The kinetic properties of the NMDA current were studied using
glutamate pulses ranging in duration from 1 to 3 sec. For all duration
applications, the currents rose slowly to a peak within 5-20
msec, producing identical peak currents. The rise time course of the
current evoked by a 1 mM, 10 msec glutamate pulse can be described by one rising exponential. The rising time constant was
6.46 ± 0.7 msec (data not shown), and the 20-80% rise time was
8.58 ± 0.78 msec across the dendrites (n = 52)
(Fig. 7A). The same current
decayed with a double-exponential time course, having time constants of
252.5 ± 21.8 msec (1, 61 ± 1.8%)
(Fig. 7B,D) and 1.66 ± 0.15 sec (2, 39 ± 1.8%) (Fig.
7C,D). There were no location-dependent
differences in the activation and deactivation kinetics of NMDA
receptor-mediated currents (p > 0.05). To
determine the time constant of desensitization, 3-sec-long glutamate
pulses were used. From 27 patches, 14 did not show any or very small desensitization, and the decay could not be fit by an
exponential function. In 13 cases, the single-exponential time constant
was 760.26 ± 66.82 msec (data not shown).
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Figure 7.
Kinetic properties of NMDAR-mediated glutamate
currents versus location. A, Mean of NMDA current
20-80% rise time for currents evoked by 10 msec application of 1 mM glutamate to outside-out membrane patches excised from
various locations of apical dendrites. B, Mean of fast
deactivation time constants (1) for NMDA currents
evoked as in A. C, Mean of slow
deactivation time constants (2) of NMDA currents
as in A and B. D, Mean of
deactivation time constant ratio of the NMDA currents evoked as in
B and C. Currents were recorded in the
presence of 10 µM glycine and in the absence of
Mg2+. Each point is an average
of five sweeps (Vh was 80 mV).
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Estimation of the proportion of synaptic receptors
It is likely that our patches contain a mix of synaptic and
extrasynaptic receptors. Therefore, we used the "irreversible" activity-dependent NMDA receptor blocker MK-801 to determine the relative amount of synaptic versus extrasynaptic NMDA receptors in our
patches (Rosenmund et al., 1995). Before pulling outside-out patches,
we used a stimulus protocol that should predominately block synaptic
receptors while leaving extrasynaptic receptors relatively
unaffected. After localized electrical stimulation (see Materials and
Methods), outside-out patches were excised from the synaptically active
regions of the dendrites. NMDA currents were then evoked using the fast
application system, and the current amplitude was monitored over time
to assess the amount of NMDA receptors blocked by MK-801. To speed the
recovery from block, patches were depolarized every second minute from
80 to +20 mV, and three to four glutamate pulses were applied for 500 msec. The proportion of current recovered from MK-801 block was used as
an relative index of the amount of synaptic receptors in the patches.
As control, we used patches excised from proximal regions of the apical
dendrite in which there are few synapses and therefore mostly
extrasynaptic receptors, as well as patches from the distal part of the
dendrite that had received no synaptic stimulation (data under these
two conditions were pooled in Fig.
8C).
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Figure 8.
MK-801 block and recovery of synaptically active
NMDA receptors. A, Dendritic recording in whole-cell
mode, during electrically evoked EPSCs (see Materials and Methods).
EPSC before (dashed line) and after (solid
line) 10 min bath application of 20 µM MK-801,
during which synaptic stimulation was given every 20 sec. The transient
component of the EPSCs (primarily carried by AMPA receptors) did not
change, whereas the slow component (primarily carried by NMDA
receptors) decreased significantly. Currents were recorded in the
presence of 10 µM bicuculline, 1 mM
Mg2+, and 0 mM added glycine.
B, NMDA-mediated current evoked by 10 msec pulse of 1 mM glutamate to outside-out patches excised near the
stimulating electrode (see Materials and Methods). Currents were
recorded in the presence of 10 µM glycine and in the
absence of Mg2+. First
trace shows a small NMDA current (0 min) because of
little relief from MK-801 block. Ten minutes later (10 min), a much
bigger current was detected as recovery had proceeded. To speed the
recovery from block, patches were depolarized every second minute from
80 to +20 mV, and three to four glutamate pulses were applied for 500 msec (see Results). Each trace is an individual sweep
(Vh was 80 mV). C, NMDA
receptor-mediated glutamate current evoked by 10 msec pulses of 1 mM glutamate current was integrated and normalized to the 0 min value and plotted against time. The charge increased rapidly with
time during the relief of MK-801 block in the case of previous
stimulation (open circles with solid
line), whereas the control shows only a slight increase
(filled circles with dashed line).
D, NMDA charge recorded after 10 min divided by the
charge of the first NMDA current (10 min/0 min) under control or test
conditions. NMDA charge increased approximately ninefold in the
stimulated cases (open bar; n = 5),
whereas in control only twofold increase was observed
(filled bar; n = 6). This
suggests that the majority of the glutamate receptors in outside-out
patches are synaptic.
|
|
Patches from distal segments of dendrites with evoked synaptic activity
showed a greater than ninefold increase in NMDA current over the 10 min
recording period (Fig. 8C) (in two cases, current increased
over 20-fold after 20 min). Control patches showed only an
approximately twofold increase for the same time course. Any significant movement of NMDA receptors between the extrasynaptic and
the synaptic receptor pools during the time course of our experiments could cause an overestimation of the number of synaptic receptors in our patches (K. R. Tovar and G. L. Westbrook,
unpublished observations). Although such complications limit our
ability to be quantitative, the data suggest that the majority of
glutamate receptors in our patches were located at synaptic sites.
| |
DISCUSSION |
Summary
We characterized the amplitude, agonist affinity, kinetics, and
single-channel properties of glutamate receptor-mediated currents and
compared these properties across a wide range of the apical dendrites
of CA1 pyramidal neurons. The main finding is that the mean amplitude
of the AMPA current at least doubles with distance from the soma. This
distance-dependent increase in AMPA receptor current could be the
result of an increased receptor number, receptor density, or some
modification of receptor properties. Modified subunit composition
(Keinänen et al., 1990; Verdoorn et al., 1991; Mosbacher et al.,
1994; Swanson et al., 1997; Dingledine et al., 1999) (for review, see
Roche et al., 1994; Soderling et al., 1994; Smart, 1997) or different
phosphorylation states (Knapp et al., 1990; Greengard et al., 1991;
Hayashi et al., 1997; Mammen et al., 1997; Benke et al., 1998; Banke et
al., 2000) can change the kinetic properties, ionic permeability,
agonist affinity, current-voltage relationship, single-channel
conductance, and maximum open probability of AMPA channels. We examined
all of these receptor properties and compared them with distance from the soma and found no significant differences in any of them, whereas
on the other hand, channel number increased approximately twofold.
These data then strongly suggest that the distance-dependent increase
in AMPA current is attributable to a progressive increase in the
number of AMPAR in the patches and not to alterations in the basic
properties of the receptor-channels.
Most of our results, AMPA receptor agonist affinity, rise time,
single-channel conductance, and the concentration dependence of AMPA
and NMDA current kinetics, fit well with those published previously for
similar experiments (Jonas and Sakmann, 1992; Spruston et al., 1995).
There are, however, slight differences in deactivation and
desensitization time constants for both receptor types (AMPA and NMDA).
The kinetics reported here are slightly faster than those reported
previously, and this difference is likely to be attributable to
developmental changes occurring in the receptors (our data being from
adults and theirs from juveniles) (Jonas and Sakmann, 1992; Spruston et
al., 1995). The calculated P0,max reported here is greater than that reported previously (Spruston et
al., 1995), and this is surely the result of our use of a higher glutamate concentration (10 mM vs 1 mM) for the nonstationary fluctuation analysis
experiments (Silver et al., 1996). Finally, this is the first
report of a distance-dependent increase in AMPA current amplitude, and
this too may be attributable to age differences or to the limited
distance of the previous dendritic recordings (<175 µm) (Spruston et
al., 1995).
Implications for distance-dependent synaptic scaling
These data fit well with the previous finding that the average
conductance of Schaffer collateral synapses increases approximately twofold with distance from the soma and, as expanded on below, suggest
that an increase in AMPA receptor numbers may be a primary mechanism of
this increased conductance. The postsynaptic densities (PSDs) of
Schaffer collateral synapses show a wide range of sizes, and the number
of AMPA receptors present at these synapses increases directly with the
PSD length (Takumi et al., 1999). Furthermore, spine head volume, PSD
area, and presynaptic terminal volume and active zone (AZ) areas all
vary together and show a wide range of sizes (Nusser et al., 1998;
Schikorski and Stevens, 1999).
In light of these data, it seems possible that the average size of the
Schaffer collateral synapses could increase with distance from the
soma. In fact, similar changes have already been observed in other
central neurons. The size and complexity of various presynaptic and
postsynaptic components, including glycine receptor clusters, increases
with distance from the soma of Mauthner cells (Triller et al., 1990;
Sur et al., 1995). Furthermore, the size of gephyrin clusters, a
protein involved in the clustering of glycine receptors, increases in
size and complexity with distance from the soma of motoneuron and Ia
inhibitory interneurons (Alvarez et al., 1997). Thus, the distal
regions of CA1 pyramidal neuron dendrites may possess a greater number
of large area Schaffer collateral synapses that contain more AMPA
receptors, and we were able to observe this increase as
larger-amplitude AMPA currents.
AMPA and NMDA receptors are colocalized in at least 75% of Schaffer
collateral synapses (Takumi et al., 1999), and the ratio of receptor
numbers changes as a linear function of PSD diameter. Although the
number of AMPA receptors showed a linear correlation to PSD area, the
NMDA receptor numbers were independent of synapse size. Our patch data
are consistent with these data in that the NMDA receptor number remains
constant regardless of distance from soma. That NMDA receptor number
remains constant whereas AMPAR numbers increase suggests that the
observed increase in AMPA receptor current is not attributable to any
distance-dependent changes in patch area, spine density, or receptor access.
That we observed distance-dependent changes in some of the postsynaptic
properties of Schaffer collateral synapses does not exclude the
possibility of other synaptic changes as well. In fact, because the
size of the axon terminal, AZ, and number of docked vesicles all change
together with postsynaptic properties, it is likely that presynaptic
modifications exist wherever there are postsynaptic changes.
Furthermore, as with other synapses, Schaffer collateral terminals are
capable of releasing multiple quanta from multiple release sites (Sorra
and Harris, 1993; Bolshakov et al., 1997; Larkman et al., 1997;
Bykhovskaia et al., 1999; Prange and Murphy, 1999). Theoretically, the
occurrence of multisynaptic boutons or the number of release site per
bouton could also increase with distance from soma (Sur et al., 1995;
Larkman et al., 1997). Any of these changes can cause an elevated
synaptic conductance, and, given the covariance of many of these
synaptic properties, it seems likely that many changes together will be
responsible for the increased conductance of distant synapses.
The above discussions rely on the accuracy of previous reports stating
that spine density (spines per square micrometer) is uniform
throughout the areas of radiatum innervated by the Schaffer collaterals
in rodent hippocampal slices (Andersen et al., 1980; Bannister and
Larkman, 1995; Trommald et al., 1995). If, on the other hand, spine
density does increase with distance (Megías et al., 2001), then
obviously this elevated synapse density could contribute to our
observed increase in AMPA current with distance. The role that any such
increase in synapse density would play in distance-dependent synaptic
scaling is unknown.
Mechanism of distance-dependent scaling
For synapses to use a distance-dependent scaling to remove the
location dependence of synaptic efficacy requires these synapses to
have some indication of their physical location in the dendritic arborization. This leads to the following important questions: what
signals are available to provide synapses with a distance-dependent cue, and how might this signal be translated into changes in synaptic strength? To us, it seems most likely that the distance-dependent regulation of AMPA receptor numbers and synaptic conductance are under
the control of mechanisms similar to those described for homeostatic
plasticity (Turrigiano et al., 1998; Turrigiano and Nelson,
2000). In homeostatic plasticity, synaptic currents are scaled relative
to postsynaptic activity, with action potential blockade leading to
increases in EPSC amplitude, postsynaptic glutamate responsiveness,
AMPAR half-life, and AMPAR numbers. Along these lines, it is now well
appreciated that the amplitudes of dendritic action potentials and the
calcium influxes associated with them are dependent on distance from
the soma, with both decreasing in amplitude with distance (Magee et
al., 1998). Furthermore, there is some evidence that resting cytosolic
[Ca] is reduced with distance from the soma (Magee et al., 1996).
Together, these observations lead us to propose that the reduced
excitability of the distal dendrites alter the structure and
composition of the synapses located there in a manner that increases
their unitary conductance.
In conclusion, we observed a distance-dependent increase in the
amplitude of AMPA receptor-mediated currents in the apical dendrites of
CA1 pyramidal neurons. The magnitude of this increase closely matches
that observed for Schaffer collateral synapses across the same range of
dendritic regions. In light of this observation and because no
differences in a variety of AMPA channel properties were observed, we
conclude that an increase in the amount of AMPA receptors elevates the
conductance of distant Schaffer collateral synapses in hippocampal CA1
pyramidal neurons.
| |
FOOTNOTES |
Received June 6, 2001; revised Aug. 20, 2001; accepted Sept. 17, 2001.
This work was supported by National Institutes of Health Grant
NS 35865 and NS 39458 and the Alfred P. Sloan Foundation.
Correspondences should be addressed to Bertalan K. Andrásfalvy,
Neuroscience Center, Louisiana State University Health Science Center,
2020 Gravier Street, New Orleans, LA 70112. E-mail: bandra{at}lsuhsc.edu.
| |
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M. Rudolph and A. Destexhe
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M. Eder, W. Zieglgansberger, and H.-U. Dodt
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W. B Levy and R. A. Baxter
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TOP
ABSTRACT
INTRODUCTION
