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Next Article 
Volume 16, Number 15,
Issue of August 1, 1996
pp. 4537-4542
Copyright ©1996 Society for Neuroscience
Apical Dendritic Location of Slow Afterhyperpolarization Current
in Hippocampal Pyramidal Neurons: Implications for the Integration of
Long-Term Potentiation
Pankaj Sah1 and
John M. Bekkers2
1 Neuroscience Group and the Discipline of Physiology,
University of Newcastle, New South Wales, Australia, and
2 Division of Neuroscience, John Curtin School of Medical
Research, Australian National University, Canberra, Australia
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Trains of action potentials in hippocampal pyramidal neurons are
followed by a prolonged afterhyperpolarization (AHP) lasting several
seconds, which is attributable to the activation of a slow
calcium-activated potassium current (sIAHP). Here
we examine the location of sIAHP on CA1 pyramidal
neurons by comparing it with two GABAergic inhibitory postsynaptic
currents (IPSCs) with known somatic and dendritic locations. Whole-cell
patch-clamp recordings were made from CA1 pyramidal neurons in acute
hippocampal slices. Stepping the membrane potential at the peak of
sIAHP produced a relaxation (``switchoff'') of
the AHP current with a time constant of 7.4 ± 0.4 msec (mean ± SEM). The switchoff time constants for somatic and dendritic
GABAA IPSCs were 3.5 ± 0.5 msec and 8.8 ± 0.3 msec, respectively. This data, together with cable modeling, indicates
that active sIAHP channels are distributed over
the proximal dendrites within ~200 µm of the soma. Excitatory
postsynaptic potentials (EPSPs) evoked in stratum (s.) radiatum had
their amplitudes shunted more by the AHP than did EPSPs evoked in s.
oriens, suggesting that active AHP channels are restricted to the
apical dendritic tree. Blockade of the AHP during a tetanus, which in
control conditions elicited a decremental short-term potentiation
(STP), converted STP to long-term potentiation (LTP). Thus, activation
of the AHP increases the threshold for induction of LTP. These results
suggest that in addition to its established role in spike frequency
adaptation, the AHP works as an adjustable gain control, variably
hyperpolarizing and shunting synaptic potentials arising in the apical
dendrites.
Key words:
AHP;
cable analysis;
dendrite;
long-term potentiation;
potassium channel;
short-term potentiation
INTRODUCTION
Calcium influx during action potentials activates
two distinct types of calcium-dependent potassium currents in
hippocampal pyramidal neurons. One of these currents
(IC) is active during action potential
repolarization, whereas the other, a slow calcium-activated potassium
current (sIAHP), causes a prolonged
afterhyperpolarization (AHP) that follows trains of action potentials
and leads to spike frequency adaptation (Madison and Nicoll, 1984 ;
Lancaster and Nicoll, 1987). It is now clear that although BK-type
calcium-activated potassium channels underlie IC
(Lancaster and Nicoll, 1987), the sIAHP is
generated by a different type of channel that is distinct from BK or SK
channels (Sah, 1996).
It has generally been assumed that active AHP channels are uniformly
distributed over the surface of CA1 pyramidal neurons (Traub et al.,
1991; Jaffe et al., 1994), although there is no direct evidence to
support this view. Because the activation of
sIAHP is triggered by calcium influx via
voltage-gated calcium channels (Hotson and Prince, 1980; Schwartzkroin
and Stafstrom, 1980; Sah and Isaacson, 1995), the distribution of
calcium channels may provide clues about the localization of activated
AHP channels. L-type calcium channels are concentrated near the soma
and particularly at the origins of the major dendrites, whereas N-type
channels are widely distributed over the dendritic membrane (Ahlijanian
et al., 1990; Westenbroek et al., 1992; Mills et al., 1994). It is
becoming clear that different types of calcium channels selectively
activate different calcium-activated potassium currents (Viana et al.,
1993; Sah, 1995). Furthermore, calcium imaging experiments indicate
that after action potentials, the highest levels of intracellular
calcium are achieved in the proximal dendrites (Miyakawa et al., 1992;
Regehr and Tank, 1992; Jaffe et al., 1994; Spruston et al., 1995). This
raises the possibility that activated AHP channels also may have a
restricted dendritic localization. Indeed, active AHPs can be recorded
from the apical dendrites (Lancaster and Zucker, 1994; Andreason and
Lambert, 1995). Because the AHP has a very slow time course (Lancaster
and Adams, 1986; Sah and Isaacson, 1995) and responds to both calcium
influx and many neuromodulators (Nicoll, 1988), an inhomogeneous
distribution of active AHP channels would have major implications for
the processing and integration of synaptic inputs.
In this article we address the question of the location of functioning
AHP channels in hippocampal pyramidal neurons. Our findings indicate
that these channels are selectively located in the proximal apical
dendritic tree. Somatic AHP channels seem to contribute little to the
net AHP conductance in these neurons.
MATERIALS AND METHODS
Electrophysiology. Hippocampal slices (400 µm
thick) were prepared from 18- to 21-d-old rats using standard
techniques (Sah and Isaacson, 1995). Slices were superfused with a
Ringer's solution containing (in mM): 119 NaCl, 2.5 KCl,
1.3 Mg2SO4, 4.5 CaCl2, 1 NaH2PO4, 26.2 NaHCO3, and 11 glucose, which was equilibrated with 5% CO2/95%
O2. Patch electrodes were filled with an internal solution
containing (in mM): 135 KMeSO4, 8 NaCl, 10 HEPES, 2 Mg2ATP, and 0.3 Na3GTP, pH
7.3 with KOH (osmolarity 290 mOs/kg). Whole-cell patch-clamp recordings
were obtained from CA1 pyramidal neurons using the ``blind'' approach
(Blanton et al., 1989). Currents were recorded using an Axopatch-1D
(Axon Instruments, Foster City, CA; bandwidth >10 kHz), filtered at 5 kHz, and sampled at 10 kHz using pClamp software (Axon Instruments).
sIAHPs were evoked by a 50-200 msec depolarizing
voltage step to 0 mV. Series resistance was monitored carefully and
noted for each cell. In experiments where GABAA
inhibitory postsynaptic currents (IPSCs) were measured,
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 µM) and
D-2-amino-5-phosphonopentanoic acid
(D-APV; 50 µM) were added
to the perfusing medium to block polysynaptic events and reduce the
spread of excitation. Somatic IPSPs were evoked by a bipolar
stimulating electrode placed on the surface of the slice over stratum
(s.) pyramidale. Dendritic IPSCs were evoked by placing another
stimulating electrode near the border of s. radiatum and s. lucidum
(Pearce, 1993). To measure the time course of the ``switchoff,'' the
reversal potential of the GABAA IPSC was
measured, and then the holding potential was set 15 mV more
depolarized. Steps from this holding potential ( 48 to 51 mV) to the
reversal potential were alternated with and without stimulation of the
afferents. Traces were pairwise-subtracted, and 10 such subtractions
were averaged. A similar procedure was used for the AHP switchoffs,
except that a 15 mV hyperpolarizing step was always made from 50 mV.
AHP and GABA switchoffs were bracketed several times on the same cell,
and series resistance was checked for stability before and after each
set of subtractions. Note that to facilitate comparisons, the stimulus
intensity for the IPSCs was adjusted to elicit currents similar in
amplitude to the AHP current measured in the same cell.
In experiments measuring shunting of basal and apical excitatory
postsynaptic potentials (EPSPs), stimulating electrodes were placed in
s. oriens and in the distal third of s. radiatum, and picrotoxin (100 µM) was added to block
GABAA synaptic potentials that may have
contaminated the peak of the synaptic potential. We noted that a higher
concentration of isoprenaline (10 µM) was
needed to block the AHP in whole-cell recordings (see Fig.
3C), compared with intracellular or field recordings
(0.1-0.2 µM) (Madison and Nicoll, 1986) (see
Fig. 4), perhaps because of partial washout. This higher concentration
produced a small inhibition of EPSPs (see Fig. 3C,
right). For LTP experiments, field EPSPs were recorded using
a Ringer's solution-filled patch electrode. In each slice, an
input/output curve was first measured, and the field EPSP amplitude was
adjusted so that a half-maximal response was obtained.
Fig. 3.
The AHP is preferentially located in the apical
dendritic tree. A, Experimental paradigm. EPSPs were evoked
with (asterisk) or without a preceding depolarizing current
injection to activate the AHP. B, Current-clamp recordings
were obtained from the soma, and EPSPs were evoked either in s.
radiatum (radiatum) (a) or in s. oriens
(oriens) (b). Fast IPSPs were blocked with
picrotoxin (100 µM). Superimposed, baselined
EPSPs are shown on the right with (asterisk) and
without a concurrent AHP. The amplitude of the EPSP evoked in
radiatum was preferentially shunted in comparison to the
EPSP evoked in oriens. Note that the faster decay of the
EPSPs with an AHP reflects the faster membrane time constant of the
whole cell when the AHP is active. C, Control experiment
showing that when the AHP is blocked by 10 µM
isoprenaline (Iso, right), the shunting of the
apical EPSP is absent. Asterisks identify the EPSPs obtained
after the AHP-inducing stimulus.
[View Larger Version of this Image (16K GIF file)]
Fig. 4.
Blockade of the AHP converts STP into LTP.
A, Graph of normalized field EPSP slope against time from
experiments (n = 5 slices) where a weak tetanus
(W; 50 Hz, 0.5 sec) was applied first by itself and then
after blockade of the AHP with isoprenaline. A decremental potentiation
(STP) is elicited by the first weak tetanus. When the AHP is blocked by
isoprenaline (Iso; 0.2 µM), the same
weak tetanus now elicits LTP. Sample field EPSPs are shown below for
the times indicated. B, Graph of normalized field EPSP slope
against time from experiments (n = 5 slices) where a
weak tetanus (W; 50 Hz, 0.5 sec) was applied first by itself
and then in the presence of isoprenaline plus propranolol (Iso + Propranolol) to block  -adrenergic receptors. Both times, the
weak tetanus elicited STP. A subsequent strong tetanus (S;
100 Hz, 1 sec) elicited LTP, indicating that the slices were capable of
potentiation. Sample field EPSPs are shown below for the times
indicated.
[View Larger Version of this Image (21K GIF file)]
Switchoff experiments were carried out at 30°C to increase the
amplitude of the AHP and speed up its time course; shunting and LTP
experiments were carried out at room temperature (~22°C).
Statistical comparisons were made using the paired t test.
All chemicals were obtained from Sigma (St. Louis, MO) except CNQX and
D-APV, which were from Tocris Neuramin (Bristol,
UK).
Cable modeling. Simulations were performed using NEURON, a
program for numerically solving the cable equations in a compartmental
model of a neuron (Hines, 1993). The model used the CA1 pyramidal cell
shown in Figure 4 of Major et al. (1993), after its apical dendrites
were collapsed further into a single equivalent dendrite. The accuracy
of the collapsed model, compared with the full model, has been
confirmed by Major et al. (1993). Equivalent cylinders were divided
into compartments that were  10 µm (<0.01  ). The passive
properties of the model neuron were assumed to be uniform, with
Ri = 100  cm,
Cm = 0.7 µFcm 2
(Major et al., 1993), and Rm chosen so that
the model gave the input resistance measured for each neuron
(Rm range 40-50
kcm2). The model also incorporated the
electrode series resistance measured for each switchoff experiment
(range 8-15 M). The somatic leak conductance
was set at zero (Spruston and Johnston, 1992). For each simulation, the
GABA or AHP conductance was either injected at a single site on the
equivalent apical dendrite or was given a constant density
(S/µm2) over one or more equivalent
cylinders. First, under simulated voltage clamp at the soma (without
switchoff), both the amplitude and time course of the conductance were
adjusted to match the current observed experimentally at the soma. The
simulated switchoff current was then calculated and compared with the
experimental trace. This process was repeated for many different
injection sites or distributions over the equivalent dendrite. For the
EPSP shunting simulations, the same model neuron was used in current
clamp. The EPSP conductance was assumed to be described by an  function with  = 3 msec and was injected at a point 300 µm from
the soma into the equivalent basal or apical dendrite.
GABAA-mediated synaptic currents are weakly
voltage-dependent (Collingridge et al., 1984); however, including this
voltage-dependence in the model had minimal effects on the time course
of the switchoff. The current underlying the AHP is voltage-independent
(Lancaster and Adams, 1986).
RESULTS
We have used an indirect route to address the question of the
location of active AHP channels. Consider a perfectly space-clamped
cell that has a voltage-independent conductance. If the cell is
voltage-clamped at a potential different from the reversal potential, a
steady current will be measured by the voltage clamp. If the clamp
potential is suddenly stepped to a different value, the membrane
potential and membrane current will relax to their new values, with a
time course determined by the speed of the voltage-clamp circuit, the
series resistance of the electrode, and the capacitance of the cell
(Jackson, 1992). In an extended structure such as a pyramidal neuron,
however, distant dendritic membrane will settle more slowly to the new
membrane potential after a voltage step imposed at the soma, because of
the cable properties of the dendrites (Jack et al., 1983). As a
consequence, relaxation of the membrane current arising in distant
membrane will also be slowed, and current of increasingly distant
origin will be slowed to an increasing extent (for review, see Spruston
et al., 1994).
To test this prediction we took advantage of the anatomy of hippocampal
pyramidal neurons, which receive fast inhibitory synaptic inputs from
two distinct sets of GABAergic interneurons. One set forms baskets of
synapses around the somas of pyramidal neurons (Andersen et al., 1964).
The other set forms inhibitory synapses on the apical dendritic tree
(Alger and Nicoll, 1982a). These two sets of interneurons can be
stimulated selectively in vitro in a transverse hippocampal
slice (Alger and Nicoll, 1982a; Pearce, 1993).
CA1 pyramidal neurons were voltage-clamped near 50 mV, and inhibitory
postsynaptic currents (IPSCs) were evoked either by stimulation in the
cell body region (somatic IPSC) or in s. radiatum (dendritic IPSC; Fig.
1A). Both IPSCs were blocked
completely by picrotoxin (100 µM;
n = 3), confirming that they were mediated by
GABAA receptors. Near the peak of the synaptic
current, the membrane potential was stepped to the reversal potential
of the IPSC (near 65 mV). After the voltage step, the synaptic
current relaxed to its new value with a time course that was faster for
the somatic IPSC ( = 3.5 ± 0.5 msec, mean ± SEM;
n = 5) than for the dendritic IPSC ( = 8.8 ± 0.3 msec; n = 4), consistent with its electrotonically
closer location to the recording electrode at the soma
(p < 0.001, paired t test; Fig.
1B). Note that the somatic relaxation is not instantaneous
because the voltage-clamp step at the soma is slowed by the resistance
of the electrode in series with the cell capacitance (Jackson, 1992).
To determine the relaxation time course for the AHP current,
sIAHP was evoked by a 50-200 msec step to 0 mV
from a holding potential of 50 mV. Near the peak of the outward
current, the membrane potential was stepped to 65 mV. The current
relaxed to its new value with a time constant of 7.4 ± 0.4 msec
(n = 8), slower than that for the somatic
GABAA IPSC (p < 0.001),
but not significantly different from that for the dendritic IPSC
(p > 0.05; Fig. 1C). These results suggest
that active AHP channels are not concentrated on the soma.
Fig. 1.
Current generating the AHP has a more distal
distribution than current underlying the somatic GABAergic IPSC.
A, Schematic diagram illustrating the experimental setup.
The cell was voltage-clamped at the soma at a holding potential of 50
mV. Somatic and dendritic inhibitory postsynaptic currents (IPSCs) were
independently stimulated in s. pyramidale and s. radiatum,
respectively. Excitatory postsynaptic currents were blocked with CNQX
(10 µM) and D-APV (50 µM). B, a and
c show superimposed traces with and without a voltage step
to the IPSC reversal potential (65 mV). The stimulus protocol is
shown in the inset; arrow indicates synaptic
stimulation. The relaxations after the voltage step are shown expanded
in b and d and have been fitted with a single
exponential for comparison. As expected for an electrotonically distant
input, the dendritic IPSC (a, b) relaxed at a
slower rate ( = 10 msec) than the somatic IPSC (c,
d; = 3.7 msec) recorded in the same cell. C,
The AHP current in the same neuron, with and without a voltage step to
65 mV (a). The current relaxation is shown expanded in
b and has been fitted with a single exponential. The AHP
current relaxed with a time course ( = 8.3 msec) slower than that of
the somatic IPSC, indicating that it must have a large contribution
from extra-somatic channels. Calibration: 50 pA, 20 msec (B,
a and c); 50 pA, 200 msec (Ca).
[View Larger Version of this Image (22K GIF file)]
To estimate the electrotonic locations on the neuron that would be
compatible with these relaxation times, we constructed an equivalent
cable model of a CA1 pyramidal cell (Fig. 2C;
for details, see Materials and Methods). Varying the distribution of
the synaptic conductance over the model cell, we found that the somatic
GABAA relaxation was simulated best when the
conductance was placed on the soma of the model (Fig.
2A,B, left panels, and 2Ca,
filled region). In contrast, the AHP current relaxation was
fitted best when the conductance change was either distributed over the
equivalent proximal dendrite within ~200 µm of the soma (Fig.
2Cb, filled region) or injected at a point
50-100 µm from the soma (Fig. 2Cb, arrow) in
different cells (n = 5; Fig. 2A,B,
right panels). The AHP relaxation was clearly not fitted by
a conductance concentrated at the soma. For the dendritic
GABAA transient, the conductance had to be
distributed further out in the dendrite, or injected at a point
100-125 µm along the equivalent dendrite from the soma, to predict
correctly the transient (not shown). In two cells, we were also able to
measure a GABAB IPSC that is thought to have a
distant dendritic location (Alger and Nicoll, 1982b). In both cases,
the time course of the relaxation was very slow (time constants 16.9 and 16.5 msec), consistent with a distant location for this
conductance.
Fig. 2.
Electrotonic locations of the AHP and somatic
GABAA IPSC channels, estimated using an
equivalent cable model of a CA1 pyramidal neuron. A, Somatic
IPSC (left) and AHP current (right) recorded in
the same cell, when interrupted by a step from the holding potential
(50 mV) to 65 mV. B, The same currents shown expanded,
with predictions from the model superimposed (dashed lines).
Labels a-c correspond to different channel distributions in
the model shown in C. Trace a (soma) best fits
the IPSC switchoff, and trace b (proximal apical dendrite)
best fits the AHP. C, Schematic diagram showing the
equivalent cylinder model used to fit the data. The dendritic trees
(apical at right) are shown to scale, using a different
scale for the lengths and diameters, but the soma (circle)
is not to scale. Filled regions represent the membrane
surface that was given a constant conductance density: a,
soma only; b, initial 166 µm of the apical dendrite;
c, all of the apical dendrite. Adding the same conductance
density to the soma made little difference to the predictions of models
b and c, because the soma has a much smaller
surface area than the dendrites. The arrow in b
is 75 µm from the soma; injecting the AHP conductance at this point
gave an identical switchoff to the distributed conductance in
b.
[View Larger Version of this Image (23K GIF file)]
Hippocampal pyramidal neurons are polarized cells with a basal and an
apical dendritic tree. We next asked whether the AHP conductance was
located preferentially in either or both trees. To address this
question, we took advantage of the laminar nature of the excitatory
synaptic inputs to pyramidal neurons (Andersen et al., 1980). Because
the decay time constant of the excitatory synaptic currents (3-5 msec;
Hestrin et al., 1990) is faster than the membrane time constant (20-30
msec; Spruston and Johnston, 1992), the peak amplitude of a
subthreshold EPSP reflects the local input impedance rather than the
impedance of the whole cell (Carlen and Durand, 1981). EPSPs were
evoked in either s. radiatum or s. oriens, alone or during the AHP
(Fig. 3A). The peak amplitude of the EPSP in
s. radiatum was reduced during the AHP (to 0.81 ± 0.04 of control,
mean ± SEM; n = 8), whereas the EPSP evoked in s.
oriens was affected marginally (0.98 ± 0.07; n = 8;
Fig. 3B; s. radiatum and s. oriens are significantly
different: p < 0.05). When the AHP was blocked by
application of isoproterenol (10 µM;
n = 3) or carbachol (1 µM;
n = 2), the shunting of the EPSP after a depolarizing
voltage step was blocked completely (Fig. 3C). This result
indicates that AHP channels are located preferentially in the apical
dendritic tree. These observations were also reproduced by the model
(not shown; see Materials and Methods).
What are the physiological consequences of a dendritic location of the
AHP? The action of the AHP in shunting the amplitude of local EPSPs is
reminiscent of shunting inhibition (Carlen and Durand, 1981).
Inhibitory inputs to pyramidal neurons have a significant effect on
processes requiring synaptic integration. In particular, blockade of
GABAA inhibition reduces the threshold for the
induction of long-term potentiation (LTP) (Wigstrom and Gustafsson,
1983). We thus tested whether activation of the AHP has a similar role.
Field EPSPs in area CA1 were evoked at a frequency of 0.1 Hz. After a
stable baseline was obtained, a weak tetanus (50 Hz, 0.5 sec) was
delivered, which caused a potentiation that returned to baseline over
the next 30 min (Fig. 4A). The AHP was then
reduced by application of the selective -adrenergic agonist
isoprenaline (Madison and Nicoll, 1986a). This concentration of
isoprenaline had no effect on the control EPSP (Fig. 4A) or
on the inhibitory postsynaptic potential (n = 2; not
shown); however, the same weak tetanus delivered in the presence of
isoprenaline produced a sustained potentiation (Fig. 4A;
n = 5 slices). When the actions of isoprenaline at receptors were blocked by co-application of the selective antagonist
propranolol, the second weak tetanus also led to decremental
potentiation, whereas a subsequent strong tetanus (100 Hz, 1 sec)
produced a sustained potentiation (Fig. 4B).
DISCUSSION
In this article we have studied both the electrotonic location of
the slow AHP current in hippocampal pyramidal neurons and its possible
physiological role. We conclude that this current is localized to the
proximal apical dendritic tree (within ~200 µm from the soma in the
equivalent cable model), but relatively little of the current
originates on the soma itself. This is based on two lines of evidence.
(1) The switchoff of the AHP current was slower than that for a
conductance located at the soma (Fig. 2), and (2) the amplitudes of
EPSPs evoked in s. radiatum were shunted to a larger extent than those
of EPSPs evoked in s. oriens (Fig. 3). If AHP channels were largely
somatic, both EPSPs would be equally shunted (Carlen and Durand, 1981;
our unpublished simulations). Note that our measurements can localize
only active AHP channels; this distribution may reflect the
inhomogeneous influx of calcium rather than the distribution of AHP
channels themselves.
Although these experiments show clearly that the AHP conductance is not
restricted to the somas of CA1 pyramidal cells, our conclusion about
its exact dendritic location is obviously model-dependent. We have made
three assumptions in our simulations. (1) The neuron is purely passive,
apart from the GABA, AHP, or EPSP conductances, (2) its passive
properties are uniform, and (3) the conductances are either distributed
uniformly over the surface of the model cell or injected at a single
point on the equivalent dendrite. Assumption 1 seems to hold for the
small (15 mV) hyperpolarizing voltage steps used here, because no
time-varying currents, apart from the capacity transients, were
apparent during the step without the AHP or IPSC. Even if such currents
were present, they are unlikely to have been affected by the presence
or absence of a small synaptic or AHP conductance and would have been
subtracted out in our protocol. Assumption 2 is commonly accepted
(Spruston and Johnston, 1992). Assumption 3 is the most parsimonious
one that yields good fits to the data, although other more
heterogeneous distributions may fit the switchoffs equally well.
Nevertheless, it is qualitatively clear from our simulations that the
active AHP conductance cannot be concentrated at the soma, and neither
can it be significant in the distal dendritic tree (Fig.
2B,C). Note that distance along the equivalent dendrite is
not a simple function of dendritic distance in the real cell, because
it depends on the branching pattern. The first 100 µm or so of the
apical tree of CA1 pyramidal cells, however, is dominated by a single
thick process emanating from the soma (Major et al., 1993), and so for
this region, dendritic distance will be nearly the same for both real
and equivalent cells. It is attractive to suppose that AHP channels are
concentrated here so they can act to gate incoming signals from more
distal parts of the apical dendritic tree.
Tetanic stimulation of afferent fibers in area CA1 can lead to the
generation of a form of synaptic plasticity called LTP. LTP is
triggered by depolarization of the postsynaptic cell attributable to
summation of EPSPs and unblock of NMDA channels, which allows the
influx of extracellular calcium (Bliss and Collingridge, 1993). Tetani
delivered at lower frequencies, below the threshold for induction of
LTP, give rise to a decremental form of potentiation called short-term
potentiation (STP) (Malenka, 1991). During trains of afferent stimuli,
summation of EPSPs and generation of action potentials also activate
the AHP (Nicoll, 1988; Sah, 1996). This would reduce calcium influx
through NMDA channels both directly, via the AHP hyperpolarization, and
indirectly, by shunting EPSPs and reducing their depolarizing drive
(Fig. 3). Blockade of the AHP during a given tetanus would therefore
result in a larger depolarization, a larger calcium influx, and a lower
threshold for the induction of LTP (Fig. 4; also see Hopkins and
Johnston, 1981). Because activation of the AHP is relatively slow,
these experiments lend support to the idea that some minimum duration
of calcium influx is necessary to convert STP to LTP (Malenka, 1991;
Malenka et al., 1992). It is notable that the threshold for LTP
induction is lower in basal than in apical dendrites, a difference that
is largely abolished by application of forskolin (Arai and Lynch,
1992). Forskolin increases cyclic AMP levels and blocks the AHP
(Madison and Nicoll, 1986b). Thus, this finding is consistent with an
apical location for AHP channels.
A number of neurotransmitter systems, including acetylcholine and
norepinephrine, act via distinct second messenger systems to block the
slow AHP. It is interesting that both cholinergic and monoaminergic
transmitter systems have been implicated in the consolidation of memory
(Squire, 1987). Activation of these systems and the subsequent blockade
of the AHP would facilitate the induction of LTP. Although it remains
possible that these second messenger systems interact in other ways
with the generation of LTP (Chetkovich and Sweatt, 1993), blockade of
the AHP could be one mechanism whereby these transmitters modulate the
induction of LTP.
In conclusion, these studies show that the conductance generating the
slow AHP in hippocampal pyramidal neurons is located predominantly in
the proximal apical dendritic tree. Activation of this conductance
during trains of action potentials acts as an adjustable gain control,
short-circuiting the apical tree and preferentially shunting synapses
impinging on the apical dendritic membrane.
FOOTNOTES
Received Feb. 20, 1996; revised May 2, 1996; accepted May 7, 1996.
This work was supported by grants from the National Health and Medical
Research Council of Australia, the Clive and Vera Ramaciotti
Foundations, and the Australian Research Council. We thank Dirk van
Helden and Stephen Redman for support, and Bob Callister, Stephen
Redman, and Bruce Walmsley for suggestions.
Correspondence should be addressed to Dr. Pankaj Sah, Neuroscience
Group, Discipline of Physiology, Faculty of Medicine and Health
Sciences, University of Newcastle, New South Wales 2308, Australia.
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