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The Journal of Neuroscience, January 1, 1998, 18(1):438-450
Spatial Distribution of Potentiated Synapses in Hippocampus:
Dependence on Cellular Mechanisms and Network Properties
M. F.
Yeckel and
T. W.
Berger
Department of Biomedical Engineering, Program in Neuroscience,
University of Southern California, Los Angeles, California 90089-1451
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ABSTRACT |
Long-term potentiation (LTP) of synaptic transmission, studied
intensively in reduced brain preparations such as hippocampal brain
slices, is the leading candidate for the cellular/molecular basis of
learning and memory. Serious consideration of LTP as underlying
information storage in the intact brain, however, requires understanding how LTP can be induced selectively at specific synaptic sites in a neural system when the mechanisms underlying LTP are regulated by other structural and functional properties of the same
neural system. In the studies reported here, we tested the hypothesis
that different patterns of activity within the same population of
entorhinal cortical afferents could lead to a selective potentiation of
spatially distinct populations of synapses across different regions of
the hippocampus, including those activated multisynaptically. We
focused specifically on potentiation of direct, monosynaptic entorhinal
input to dentate granule cells, which expresses an NMDA
receptor-dependent LTP, and on potentiation of indirect, disynaptic
entorhinal input to CA3 pyramidal cells, which is transmitted by the
mossy fiber projection of dentate granule cells and expresses an NMDA
receptor-independent LTP. The principal findings of these experiments
show that lower stimulation frequencies (10-20 Hz) of entorhinal
cortical axons selectively induce LTP of mossy fiber input to CA3
transsynaptically via excitation of dentate granule cells, and that
patterns of stimulation of that mimic neuronal firing in the entorhinal
cortex during endogenous theta rhythm (five-impulse bursts at 200 Hz,
interburst intervals of 200 msec) induce LTP both monosynaptically for
input to dentate granule cells and transsynaptically for mossy fiber
input to CA3.
Key words:
LTP; CA3; CA1; pyramidal cell; dentate gyrus; granule
cell; mossy fiber; perforant path; entorhinal cortex; transsynaptic; in vivo; learning; memory
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INTRODUCTION |
The most promising mechanism
for the cellular/molecular basis of learning and memory is long-term
potentiation (LTP) of glutamatergic synaptic transmission (Berger,
1984 ; Landfield and Deadwyler, 1988; Morris, 1989; Bliss and
Collingridge, 1993). Intensive experimental study of this phenomenon
has revealed that LTP can be expressed by each of the synaptic
populations forming the intrinsic, input-output pathway of the
hippocampus (entorhinal cortex to dentate granule cells, granule cells
to CA3 pyramidal cells, and CA3 pyramidal cells to CA1 pyramidal
cells), and that the induction of LTP at any of these synaptic sites is
achieved when excitatory activity increases to a critical level
(McNaughton et al., 1978; Wigstrom and Gustafsson, 1983; Kelso et al.,
1986). In addition, there appear to be different "forms" of LTP
based on evidence that more than one set of mechanisms can lead to
synaptic potentiation. For example, LTP of entorhinal cortical input to
dentate granule cells requires activation of the NMDA subtype of
glutamate receptor, whereas LTP of dentate granule cell input to
pyramidal cells of the CA3 region can be induced independently of NMDA
receptor-mediated activity (Harris and Cotman, 1986; Wigstrom et al.,
1986). The dynamics of the underlying cellular/molecular mechanisms
place constraints on the patterns of afferent activity, which optimally induce synaptic potentiation. For example, NMDA receptor-dependent LTP
is preferentially induced by high-frequency (100-400 Hz) bursts of
excitatory activity, because temporal summation during the bursts is an
efficient means for providing the depolarization of the postsynaptic
neuron required to relieve the Mg2+ block of the
NMDA channel (Collingridge et al., 1988).
To date, electrophysiological studies of LTP have focused
primarily on identifying the cellular/molecular mechanisms underlying potentiation of synapses activated monosynaptically, which has necessitated the use of reduced preparations, such as in
vitro slices and tissue cultures (Andersen et al., 1977; Malenka
et al., 1988; Davies et al., 1989; Bekkers and Stevens, 1990; Foster and McNaughton, 1991). When considered in the context of the intact brain, however, additional factors related specifically to network properties may play essential roles in achieving the specific induction
requirements for LTP (Berger and Sclabassi, 1988; Berger et al., 1997).
For example, the level of depolarization that results from an
excitatory event after its propagation through a multisynaptic pathway
will be influenced substantially by the degree of progressive convergence or divergence in the series of anatomical projections comprising that circuit. Analogously, the temporal pattern of action
potential activity expressed by any one neuron in a circuit will be
determined strongly by the extent of nonlinear transformations that
occur at preceding synaptic junctions. These considerations raise the
possibility that patterns of activity that are ineffective for inducing
LTP monosynaptically may be effective for other, transsynaptically
activated, cells. This possibility is strengthened by the fact that
different mechanisms underlie LTP of synaptic connections between
different subregions of hippocampus, strongly suggesting that the most
effective pattern of activity for inducing LTP varies for different
populations of synapses.
In the studies reported here, we test the hypothesis that different
patterns of activity within the same population of entorhinal cortical
afferents can lead to selective potentiation of spatially distinct
populations of synapses with the hippocampus, including LTP of synapses
activated multisynaptically. Our studies of the hippocampus in
vivo show that selective potentiation of different synaptic sites
reflect different mechanisms of LTP induction, and that a combination
of anatomical and physiological factors determines the spatiotemporal
propagation of excitatory activity through intrinsic hippocampal
pathways.
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MATERIALS AND METHODS |
Surgical preparation. Experiments were performed on
adult, male New Zealand White rabbits anesthetized continuously with
gaseous halothane (1.5-2.0%) while body temperature was maintained at 37-39°C. All experimental procedures were consistent with those outlined in National Institutes of Health publication 91-3207, Preparation and Maintenance of Higher Animals During Neuroscience Experiments.
The skull and dura overlying the parietal cortex, dorsal to the
hippocampus, were removed, and bipolar stimulating microelectrodes (Epoxylite-insulated stainless steel 00 insect pins, with 250 µm
exposed tips and spaced 500-1000 µm apart) were positioned stereotaxically into medial perforant path fibers of the angular bundle. When examining the mossy fiber pathway, a concentric bipolar stimulating electrode (Rhodes Medical Instruments; 100 µm diameter, modified so that the total exposed length was ~350 µm) was lowered into the ventral two-thirds of the hilus of the ipsilateral dentate gyrus adjacent to the CA3c region.
Stainless steel recording microelectrodes (etched and insulated insect
pins; 10 µm exposed tip; 1 M measured at 135 Hz in vitro) or tungsten recording microelectrodes (A-M Systems; 50-100 µm; 4-12 M measured at 1 kHz in vitro) were placed
stereotaxically into the cell body layers or the dendritic layers of
the dentate gyrus and the CA3 subfield so that evoked responses could
be recorded simultaneously from these two subfields. In some
experiments, single recording electrodes were glued to concentric
bipolar stimulating electrodes (horizontal tip separation, 100-200
µm; vertical tip separation, 500 µm) and placed such that perforant
path-evoked granule cell responses could be evaluated and mossy fibers
in the hilus could be excited. In general, perforant path-to-dentate responses and mossy fiber-to-CA3c responses were evaluated for a 1 mm
cross-section of the hippocampus, perpendicular to the long axis,
roughly corresponding to the anatomically identified mossy fiber
trajectory (Claiborne et al., 1986). At the completion of each
experiment, recording and stimulation loci were marked by passing 100 µA of current for 8-15 sec through the metal electrodes; animals
were deeply anesthetized with pentobarbital sodium and perfused
transcardially with 0.9% formalin. The brains were removed and stored
in 10% formalin for at least 2 d, and frozen sections 50 µm
thick were taken using a sliding microtome. The sectioned tissue then
was stained for metal deposits with 10% potassium ferrocyanide and
counterstained with 0.2% saffranin-O.
In some experiments, small quantities (nanoliters per minute) of
pharmacological agents were delivered with a micropressure ejection
system (15 msec impulses; 5-15 psi; 1 psi = 6.9 kPa) into the
cell body or dendritic regions.
Data collection and analysis. Stimulation pulses (0.1-0.2
msec) were delivered by using constant low frequencies (<0.2 Hz) or
pairs of pulses with interpulse intervals that varied between 10 and
200 msec. In cases in which two pathways were being assessed (e.g.,
perforant path input to the dentate and mossy fiber input to CA3),
stimulation pulses were given alternately to each pathway (0.1 Hz/pathway). In one series of experiments, 10-30 Hz stimulation (<30
pulses) was delivered to the perforant path while recording in both the
cell layers of the dentate gyrus and CA3. Three primary patterns of
stimulation trains were tested for induction of LTP: (1) 400 Hz trains,
10 impulses per train, one train/10 sec; (2) 100 Hz trains, 50 impulses
per train, one train/10 sec; and (3) 200 Hz bursts at a 10 Hz frequency
(theta burst), five impulses per burst, one burst/100 msec. Unless
indicated differently, a total of 100 impulses were given. In some
experiments, lower frequencies of stimulation (10-50 Hz) were used to
induce LTP. The stimulation patterns of these trains were similar to
the 100 Hz pattern: one to two trains of 50 pulses and one train/10
sec. Long-term potentiation was operationally defined as an increase in
population spike amplitude >120% of control response amplitude for a
minimum of 20 min.
Evoked field potentials were bandpass-filtered using low- and
high-frequency limits of 0.003 and 10 kHz, respectively. Unitary spike
events generated by single cells were recorded simultaneously and
differentiated from population field potentials using low- and
high-frequency limits of 0.1-1.0 and 10 kHz, respectively. Data were
digitized at 10-20 kHz (2400/E Series data acquisition processor,
Microstar Laboratories) on a Series 3500 HP-Apollo workstation and
stored for later analysis.
Laminar analysis was performed by lowering a recording electrode into
the dorsal hippocampus parallel to the dendritic axis of the pyramidal
and granule neurons. Recordings were started in stratum oriens of CA1,
and the electrode was lowered at increments of 50 µm until either the
ventral blade of the dentate gyrus or stratum oriens of CA3c was
reached. The tissue was allowed to stabilize for 1-2 min at each
recording site, and then three to five responses were evoked at 0.1 Hz.
Further analysis was performed on averages of the responses. In some
experiments, up to three stimulation intensities were given (intensity
ranged from threshold for activation of single action potentials in
stratum pyramidale to intensities supramaximal for evoked field
responses). Additionally, in cases in which 10 Hz stimulation trains
were given, the intertrain interval was 1 min. The one-dimensional
current-source density (CSD) at each site (x) was
calculated using the following formula:
where Ix is the current at location
x, h is the sampling distance (50 µm),
Ex is the extracellular voltage at location
x, Ex h is the extracellular voltage
at location x  h,
Ex+h is the extracellular voltage at location
x + h, and  is the tissue conductivity tensor
(for a complete treatment of the theoretical basis of CSD analysis, see
Freeman and Nicholson, 1975). The tissue (i.e., extracellular space)
was assumed to be isotropic for the pyramidal cell regions of the
hippocampus.
Because the stability of brain tissue is critical for an accurate
rendering of laminar profiles and calculated CSDs, basic physiological
function of the animal was carefully monitored, and any aberration in
breathing, heart rate, or EEG resulted in an end to the experiment.
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RESULTS |
Frequency-dependent excitation of hippocampal granule and
pyramidal neurons
The primary excitatory afferent to hippocampus originates in layer
II of the entorhinal cortex and projects monosynaptically to the
dentate gyrus and the CA3 pyramidal cell region (Lorente de Nó,
1933; Steward and Scoville, 1976; Tamamaki and Nojyo, 1993; Witter,
1993). Intrinsic projections from dentate granule cells to CA3
pyramidal neurons provide an additional cascade of excitatory input
(Swanson et al., 1978; Amaral and Witter, 1989). Thus, entorhinal
cortical and intrinsic hippocampal afferents form the basis for a
feedforward excitation of the pyramidal cell fields, such that an
excitatory volley from the entorhinal cortex excites both dentate
granule cells and hippocampal pyramidal cells simultaneously (Yeckel
and Berger, 1995b) and subsequently induces longer latency excitation
of CA3 and CA1 neurons (Yeckel and Berger, 1990, 1995b; Berger and
Yeckel, 1991).
Consistent with sequential excitation through the trisynaptic pathway,
latencies to population and single-cell responses were progressively
longer for each of the three subfields: (1) entorhinal excitation of
the dentate granule cells, 4.5-5.5 msec; (2) disynaptic excitation of
CA3, 8-13 msec; and (3) trisynaptic excitation of CA1, 16-21 msec.
The longer latency excitations of CA3 and CA1 neurons could not be
maintained in response to continuous stimulation with frequencies >25
Hz because of failure of propagation of the response across synapses,
and therefore, suggests multisynaptic excitation. The latencies of
pyramidal cell discharge also were consistent with the cumulative
monosynaptic latencies for each of the individual pathways constituting
the trisynaptic circuit: 4-6 msec for medial perforant pathway input
to granule cells, 4-7 msec for activation of CA3 by mossy fiber
stimulation, and 5-8 msec for responses of CA1 cells evoked by
Schaffer collateral stimulation. Disynaptic excitation of CA1 was
consistent with monosynaptic excitation of CA3, followed by
monosynaptic excitation via the Schaffer collaterals (Fig.
1). Inhibition of perforant path-evoked
granule cell activity by pressure ejection of the GABAA
agonist muscimol (100-500 µM) locally into the dentate
gyrus was accompanied by a suppression of long-latency responses
observed in CA3 (Fig. 2). Conversely,
local application of the GABAA antagonist bicuculline
methiodide (100-200 µM) increased granule cell
responsiveness to entorhinal input and selectively increased the
magnitude of long-latency CA3 responses (Yeckel and Berger, 1990;
Berger and Yeckel, 1991).
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Figure 1.
Serial propagation through the trisynaptic
pathway. Schematic diagram of the intrinsic organization of hippocampus
and associated physiological responses (data are from different
preparations). Top, Entorhinal innervation of the
dentate gyrus via the perforant path (pp).
Perforant path-evoked population spike in the dentate gyrus
(arrow indicates a unitary discharge).
Second from top, Mossy fiber
(mf) input to the CA3 pyramidal cell region
originating from dentate granule cells. Stimulation of granule cell
axons evokes single units (arrows) and the associated
population spike. Second from Bottom,
Innervation of the CA1 pyramidal cell region by CA3 via the Schaffer
collaterals (sch). Stimulation of CA3 axons within
stratum radiatum of CA1 resulted in a monosynaptically evoked
population spike. Bottom, Trisynaptic excitation of CA1 by 10 Hz stimulation of perforant path fibers. Single action potentials were excited at latencies corresponding to monosynaptic, disynaptic, and trisynaptic excitation. Disynaptic excitation of CA1 resulted from
monosynaptic excitation of CA3, which in turn excited CA1 monosynaptically.
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Figure 2.
Characterization of disynaptically evoked
responses in CA3 by stimulation of entorhinal afferents. The presence
of disynaptic input to CA3, via mossy fiber (mf)
input, was confirmed by selectively altering granule cell
responsiveness to perforant path (pp) stimulation and observing changes in longer-latency components of CA3 field responses. Local application of the GABAA agonist muscimol
(100-500 µM) into the dentate gyrus suppressed granule
cell responsiveness (arrow) to perforant path
stimulation (the same stimulation intensity was used for both control
and muscimol conditions) and concomitantly increased suppression of the
longer-latency component of the CA3 response (arrow).
Waveforms represent averages of five responses. Calibration bar, 5 msec
and 1 mV.
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On the basis of previous reports that stimulation of perforant path
fibers with frequencies of ~10 Hz leads to a progressive recruitment
in the number of active granule cells (i.e., frequency facilitation;
Andersen et al., 1971; Munoz et al., 1991), and on the basis of
quantitative anatomical findings that granule cell output converges
substantially in its projection to CA3 (estimates as great as 12:1;
Gaarskjaer, 1978; Amaral et al., 1990), we tested the hypothesis that
the relative strengths of monosynaptic and multisynaptic entorhinal
inputs to hippocampal pyramidal cells are frequency-dependent. Using
stimulation frequencies ranging from 1 to 30 Hz (total number of
pulses, 20-30), we found that monosynaptic excitation of pyramidal
cells by perforant path fibers occurs preferentially in response to
frequencies of electrical stimulation <5 Hz. In contrast, frequencies
of 10-15 Hz greatly enhances polysynaptic excitation of hippocampal
pyramidal neurons through the intrinsic pathways (Yeckel and Berger,
1990; Berger and Yeckel, 1991) (Fig.
3).
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Figure 3.
A, Diagrammatic representation of
the relative strengths of monosynaptic and polysynaptic excitation of
the pyramidal cell regions as a function of the frequency of entorhinal
input. Top, Stimulation frequencies <5 or >20 Hz
result predominantly in monosynaptic activation of CA3 and CA1
pyramidal neurons. Bottom, Stimulation frequencies
between 5 and 15 Hz result in enhanced excitation of pyramidal cells
transsynaptically. B, Frequency-dependent excitation of
dentate granule cells. Recruitment of granule cell activity with 10 Hz
stimulation of entorhinal afferents. Population field responses
(top) and multiunit recordings (bottom)
recorded from the granule cell layer of the dentate gyrus show
progressive facilitation of evoked responses during a 10 Hz stimulation
train (20-30 impulses). Facilitation was observed only during the
stimulation train. Calibration bar, 50 µV and 1 mV for units and
fields, respectively, and 5 msec. C, Frequency-dependent
disynaptic excitation of hippocampal CA3 pyramidal cells. Trains of
stimulation were given at frequencies of 1, 10, and 20 Hz (30 impulses
total) to perforant path fibers. Frequency-dependent excitation of
direct perforant path input to CA3 (similar to facilitation of
perforant path-to-dentate responses above) and indirect (i.e.,
disynaptic) input via the mossy fiber projection (arrows
identify monosynaptically and disynaptically evoked population spikes).
Calibration bar, 1 mV and 5 msec.
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To resolve the propagation of excitation through the intrinsic
hippocampal pathways better, CSD analysis was performed on laminar
profiles of field potentials evoked by 10 Hz stimulation of perforant
path fibers. A recording electrode was lowered into the dorsal
hippocampus at increments of 50 µm, and three 10 Hz trains of 15 impulses were delivered (intertrain interval was 1 min). Evoked
responses were averaged for each site, and estimates of the
one-dimensional CSD were generated. The results of these experiments
showed that current sinks generated by the first couple of stimulation
pulses in a 10 Hz train were short in latency (typically <7 msec), and
limited to the stratum moleculare of the dentate gyrus and stratum
lacunosum-moleculare of both the CA3 and CA1 subfields. Additional
stimulation pulses in a 10 Hz train resulted in disynaptic and
trisynaptic excitation of the pyramidal cell regions via the
trisynaptic pathway, as evidenced by longer-latency current sinks
(12-18 msec) in stratum lucidum of the CA3 subfield and stratum
radiatum of the CA1 subfield (Fig. 4).
These findings reveal that the magnitude of disynaptic and trisynaptic
excitatory input to CA3 and CA1 pyramidal neurons is predominantly
determined by the frequency of perforant path input, with 10-15 Hz
resulting in the maximum excitation.
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Figure 4.
Top. Transsynaptic excitation of CA1
pyramidal cells with 10 Hz stimulation. Contour plots of
one-dimensional CSDs computed from field responses evoked by 10 Hz
stimulation of perforant path fibers. Each panel shows the spatial and
temporal distribution of current sinks ( values) and current sources
(+ values) for a given impulse in the stimulation train (impulse
number listed above the plot). The
presence of short-latency current sinks in the distal dendritic region
of CA1 and the middle- to outer-third of dentate granule cells is
consistent with monosynaptic excitation by entorhinal afferents
(mono; monosynaptically evoked population discharges are
identified with an asterisk). A longer-latency current
sink, present in stratum radiatum of CA1, is consistent with
trisynaptic excitation of CA1 via Schaffer collaterals
(tri).
Figure 5.
Bottom. Laminar analyses of mossy fiber-evoked
responses in CA3. Data show the difficulty in distinguishing
monosynaptic and polysynaptic responses evoked by stimulation of mossy
fiber axons in the hilus. A, Laminar profile of field
potentials recorded from the proximal two-thirds of the CA3c subfield
(the region bound by the white dashed lines) while
stimulating mossy fibers in the hilus. Vertical lines
identify various components of the waveform: (1) the
line on the left (blue) shows the
onset of the mossy fiber-evoked population EPSP; (2) the middle
line (red) identifies the latency for activation of the
population spike (and contamination of the population EPSP recorded in
the dendrites); (3) the line on the right
(green) shows the latency to peak of disynaptic activation
of CA3 via the recurrent collaterals. Waveforms are averages of five
responses recorded at 50 µm increments. Calibration bar, 0.6 mV and 5 msec. B, Current-source density representation of mossy fiber
excitation. Contour plot of one-dimensional CSD identifies the spatial
and temporal distribution of current sinks ( values) and current
sources (+ values). The presence of a short-latency current sink in
stratum lucidum of CA3 (proximal apical dendrites) is consistent with
monosynaptic excitation (mono) by mossy fiber input.
Longer-latency current sinks, present in stratum radiatum of CA3 and
CA1, are consistent with disynaptic excitation (di) via the
recurrent collaterals and Schaffer collaterals, respectively.
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Frequency-dependent induction of perforant path and mossy
fiber LTP
We next examined the relationship between frequency of afferent
stimulation and the probability and magnitude of LTP induction of
monosynaptic, perforant path input to dentate granule cells and
monosynaptic, mossy fiber input to CA3 pyramidal cells. Field potentials evoked in CA3, in vivo, have not been
characterized adequately, however, so it was first necessary to
establish criteria for identification of monosynaptically evoked mossy
fiber responses (Yeckel and Berger, 1995a; Berger et al., 1997).
Distinguishing CA3 responses to mossy fiber excitation versus other
afferents is technically difficult and is an issue that remains
controversial (Williams and Johnston, 1991; Claiborne et al., 1993;
Langdon et al., 1993). Pyramidal neurons of CA3 receive four major sets
of synaptic input: monosynaptic perforant path input, mossy fiber
input, innervation by other CA3 pyramidal neurons via recurrent
collaterals, and inhibitory input from GABAergic interneurons local to
the CA3 subfield. In addition to criteria such as the presence of
orthodromic, short-latency unitary discharges in stratum pyramidale of
CA3, laminar and CSD analyses were used to identify stratum lucidum as
the location for short-latency current sinks generated in response to
hilar stimulation and to distinguish these mossy fiber-evoked responses
from other afferents such as the recurrent collaterals.
Although recordings were made from the CA3c region (proximal to the
dentate gyrus) a subregion of CA3 with a lower density of recurrent
innervation than has been reported for the CA3a and CA3b subfields (Lorente de Nó, 1933; Ishizuka et al., 1990)we still found considerable contamination of monosynaptically evoked mossy
fiber field responses by polysynaptic activation via the recurrent
collaterals. The difficulty of interpreting CA3 field responses evoked
by stimulating presumed mossy fibers in the hilus (i.e., distinguishing
the onset and slope of monosynaptic mossy fiber activation from that of
population EPSPs evoked by recurrent collaterals) is apparent with
laminar analysis of field potentials and estimations of one-dimensional
CSDs (n = 5). The results of laminar analysis showed
that mossy fiber-evoked population EPSPs recorded in stratum lucidum of
CA3 were often irregular in appearance because of the presence of
numerous single action potentials generated in nearby stratum
pyramidale of CA3 (<75 µm away). Although relatively low stimulation
intensities were used, we were not able to evoke a population EPSP
subthreshold for generation of single action potentials in stratum
pyramidale of CA3 that was detectable above background noise (Fig.
5A). Similarly, the proximity
of evoked synaptic responses to associated action potential generation
made it difficult to resolve population spikes recorded in stratum pyramidale from population EPSPs generated in stratum lucidum. In
contrast, field responses recorded in stratum radiatum, reflecting disynaptic excitation by recurrent collaterals, were smooth in appearance, similar to population EPSPs recorded in stratum moleculare of the dentate gyrus or population EPSPs recorded in stratum radiatum of CA1. Current-source density analysis confirmed stratum lucidum and
stratum pyramidale as the locations for short-latency current sinks
generated in response to hilar stimulation and showed a longer-latency
current sink in stratum radiatum (and corresponding current source in
stratum pyramidale) generated by disynaptic recurrent excitation (Fig.
5B).
Although field potentials recorded in stratum pyramidale represent a
composite of the population spike and the population EPSP, isolation of
monosynaptically evoked mossy fiber responses was performed most
accurately by recording in stratum pyramidale, where contamination
attributable to disynaptic excitation via the recurrents occurred later
in time and, as source current, could be distinguished more easily from
the current sink generated by monosynaptic mossy fiber excitation.
Mossy fiber-evoked responses were quantified by measuring the amplitude
of the negative peak of the short-latency component of the response.
As we have shown previously (Berger and Yeckel, 1991), and as has
been confirmed by others (Derrick and Martinez, 1994), high-frequency stimulation (>100 Hz) is less optimal for inducing mossy fiber LTP. As
shown in Figure 6, comparison of the
effects of 100 and 400 Hz stimulation (50-100 impulses) revealed that
100 Hz was significantly more efficient at inducing mossy fiber LTP
than 400 Hz tetanization, both in terms of probability of induction and
magnitude of potentiation (n = 5 for each frequency;
unpaired t test, p < 0.001). This is in
contrast to perforant path input to the dentate (n = 5 for each frequency), in which the probability of induction and
magnitude of potentiation were not significantly different when 100 and
400 Hz frequencies were used to induce LTP (Fig. 6A).
Additional experiments revealed that the probability of inducing mossy
fiber LTP was significantly greater for stimulation frequencies of
10-50 Hz (50-100 pulses total) than for higher frequencies of
100-400 Hz (67 and 33%, respectively); the opposite trend was found
for the probability of LTP induction of the dentate gyrus (>100 Hz,
80%; <25 Hz, 25%). Consistent with previous reports, it also was
found that stimulation frequencies as low as 10 Hz were capable of
inducing mossy fiber LTP (Zalutsky and Nicoll, 1990), whereas the
lowest frequency capable of inducing perforant path LTP was 25 Hz (Fig.
6B).
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Figure 6.
Optimal stimulation patterns differ for induction
of perforant path and mossy fiber LTP. A, Data from
representative experiments (left) in which 100 Hz
stimulation (or 400 Hz) was given to either the mossy fiber pathway or
the perforant path, followed by 400 Hz stimulation (or 100 Hz).
Regardless of the order in which the two different stimulation
frequencies were delivered to mossy fibers, 100 Hz stimulation induced
a greater-magnitude LTP than 400 Hz stimulation. Group data
(right) show that the 100 Hz stimulation protocol
induces significantly greater-magnitude mossy fiber LTP than the 400 Hz
stimulation protocol (top); similar differences were not
found for 100 and 400 Hz stimulation of perforant path fibers
(bottom) (waveforms are averages of five responses).
Calibration bar, 1 mV and 5 msec. Graphs summarize results from five
experiments for each stimulation frequency. Error bars indicate SEM.
B, The probability of inducing mossy fiber LTP was
significantly greater for lower stimulation frequencies (<50 Hz) than
for higher (>100 Hz) frequencies. In contrast, there was a greater
probability of inducing LTP of perforant path input at higher
frequencies of stimulation (>50 Hz; LTP was never induced for
perforant path input with stimulation frequencies <25 Hz).
C, LTP of mossy fiber input to CA3 is NMDA
receptor-independent. Pressure ejection of the NMDA antagonist
D-APV (50-100 µM; ~70 nl/min for 15-30
min) into the apical dendrites of CA3 and dentate granule cells
resulted in the selective blockade of perforant path LTP (for both
monosynaptic input to CA3 and the dentate gyrus; dentate population
spikes shown here) but not mossy fiber LTP (waveforms represent
averages of five responses). Calibration bar, 1 mV and 5 msec.
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The difference in optimal stimulation parameters for LTP induction of
perforant path and mossy fiber synapses may reflect the known
differences in the cellular mechanisms underlying potentiation of the
two pathways (Harris and Cotman, 1986; Wigstrom et al., 1986).
Application of the NMDA receptor antagonist D-APV (50-100 µM) blocked the induction of perforant path LTP (12 of 12 experiments, 400 Hz); recovery occurred ~30-40 min after
D-APV administration, as assessed by the ability to induce
LTP (n = 4). This is in contrast to LTP of mossy fiber
input to CA3, in which LTP was induced despite pressure ejection of
D-APV (50-100 µM) into the CA3 subfield (6 of 15 experiments, 100 Hz stimulation trains used). The lack of NMDA
receptor dependence for mossy fiber LTP confirms the interpretation that responses evoked in CA3 by hilar stimulation represent excitation of mossy fibers and not inadvertent activation of perforant path or
Schaffer collaterals, for which LTP induction is NMDA
receptor-dependent (Fig. 6C).
Transsynaptic induction of mossy fiber LTP after stimulation of
perforant path
The experiments presented thus far demonstrate that 10 Hz
stimulation of entorhinal afferents greatly enhances disynaptic excitation of CA3 pyramidal cells, and that comparable stimulation frequencies are capable of inducing LTP of mossy fiber input to CA3
cells. These findings suggest that when entorhinal activity approaches
this frequency range, there may be sufficient recruitment of granule
cell output to CA3 to reach the critical level of excitation required
for induction of LTP at mossy fiber synapses. We tested this hypothesis
by investigating whether 10-15 Hz stimulation of perforant path fibers
was capable of inducing LTP of mossy fiber input to CA3
transsynaptically via monosynaptic excitation of the dentate
gyrus and disynaptic excitation of CA3. In one series of experiments,
stimulating electrodes were placed both in the perforant path and in
the hilus of the dentate gyrus to activate mossy fiber axons of granule
cells; the possibility of mossy fiber LTP was assessed by examining CA3
responses evoked by hilar stimulation before and after stimulating the
perforant path with 10-15 or 400 Hz (Fig.
7). In support of our hypothesis, results
revealed that 10-15 Hz stimulation (50-100 impulses) of entorhinal
cortical axons induced LTP of mossy fiber input to CA3
transsynaptically via the dentate gyrus (n = 6; paired
t test, p < 0.01). LTP was not induced
transsynaptically when 400 Hz stimulation was used (eight of eight
experiments). As described previously, stimulation frequencies <25 Hz
did not induce LTP of perforant path input to the dentate gyrus (see
Fig. 6B). These data indicate that long-lasting
synaptic potentiation occurs preferentially within different subregions
of hippocampus depending on the frequency of entorhinal cortical input,
and that potentiation can occur selectively for transsynaptically
activated synapses.
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Figure 7.
Transsynaptic induction of mossy fiber LTP
with 10-15 Hz stimulation of entorhinal afferents. Top,
Schematic of experimental procedure: (1) baseline recordings were
obtained by stimulating, alternately, the perforant path
(pp) and recording evoked dentate population
spikes (right, pre) and mossy fibers
(mf) while recording evoked CA3 pyramidal cell
responses (far right, pre); (2)
stimulating the perforant path at a low frequency (10-15 Hz; 50-100
impulses); and (3) repeating part 1 to determine whether there was a
change in the magnitude of evoked responses
(post). Stimulation of perforant path fibers at
10-15 Hz resulted in LTP of mossy fiber input to CA3 transsynaptically
via monosynaptic excitation of the dentate gyrus and disynaptic
excitation of CA3. Direct, monosynaptic input to the dentate gyrus
never exhibited LTP with low-frequency stimulation trains (waveforms
represent averages of five waveforms). Calibration bar, 1 mV and 5 msec. Bottom, Summary plot of experiments in which transsynaptic LTP of mossy fiber input was induced with low-frequency stimulation of perforant path fibers (n = 6). Error
bars indicate SEM.
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Modulation of transsynaptic LTP
Results of the previous experiments predict that the probability
of entorhinal cortical input inducing LTP will depend in part on the
level of synaptic potentiation at the time of that input. Partial
support for this prediction was obtained from experiments in which
polysynaptic responses were recorded from CA3 pyramidal neurons after
monosynaptic LTP of perforant path axons. Results showed that
increasing the synaptic strength of monosynaptic entorhinal afferents
significantly decreased the number of impulses necessary to evoke
suprathreshold disynaptic and trisynaptic responses of CA3 and CA1 and
significantly increased the maximum amplitude of the evoked
polysynaptic response (Berger and Yeckel, 1991). Changes in propagation
through the hippocampus during 10-15 Hz frequency trains was examined
by computing the integrated area of the long-latency component of CA3
potentials both before and after LTP of perforant path input with 400 Hz stimulation. The region of the evoked response corresponded to
previously identified disynaptic activation (see Fig. 2). Results
showed that LTP of perforant path input significantly changed
propagation to CA3 (Fig. 8); polysynaptic
activation increased in 8 of 11 experiments in which LTP was induced
(one-way repeated measures ANOVA, F = 5.532;
p < 0.05). Two experiments were excluded from analysis because of interictal bursting that occurred during and after the
stimulation trains.
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Figure 8.
Propagation of excitation to pyramidal cells after
LTP of entorhinal afferents. A, Disynaptic responses
were evoked in CA3 with 10 Hz stimulation of entorhinal afferents (30 pulses total). After induction of perforant path-to-dentate LTP (data
not shown), propagation to CA3 increased based on the size of the late
component [disynaptic (di)] of the evoked response
(waveforms are single evoked responses recorded during a 10 Hz
stimulation train). Calibration bar, 0.4 mV and 4 msec.
B, Disynaptic propagation to CA3 increased significantly
after perforant path LTP (post pp LTP), as
assessed by the integrated area of longer-latency responses
corresponding to disynaptic excitation (n = 9).
Error bars indicate SEM.
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These data suggest that potentiation of perforant path/dentate synapses
will increase the likelihood of transsynaptic LTP induction of mossy
fiber input to CA3 pyramidal cells. This hypothesis was tested by first
stimulating perforant path fibers at a low frequency (10-15 Hz,
50-100 impulses) and with stimulation intensities subthreshold for
transsynaptic induction of mossy fiber LTP (i.e., very little
disynaptic activation of CA3 was evident during the stimulation train).
After induction of monosynaptic LTP of perforant path input with 400 Hz
stimulation, the identical low-frequency, low-intensity stimulation
parameters resulted in significantly greater disynaptic excitation of
CA3 during the stimulation train, and consequently, transsynaptic LTP
of mossy fiber input (n = 5; one-way repeated measures
ANOVA, F = 7.656; p < 0.01, using Gieser-Greenhouse correction for repeated measures) (Fig.
9).
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Figure 9.
Induction of transsynaptic mossy fiber
LTP is enabled by previous induction of perforant path LTP.
Top, Schematic of stimulation paradigm:
(1), alternate stimulation of the perforant path
(pp) and mossy fiber (mf)
path while recording in the dentate and CA3, respectively;
(2), evoked responses after low-frequency stimulation (10-15 Hz, 50-100 impulses) of perforant path fibers at intensities subthreshold for induction of transsynaptic mossy fiber LTP;
(3), high-frequency stimulation (400 Hz, 50-100
impulses) of perforant path fibers resulted in LTP of the dentate gyrus
but not mossy fiber input to CA3; (4), propagation
through the trisynaptic pathway was sufficiently enhanced after
induction of perforant path LTP so that low-frequency stimulation
[identical to that delivered in (1)] induced mossy
fiber LTP transsynaptically. Antidromic activation of dentate granule
cells was not effected. Arrows point to examples of
mossy fiber-evoked single units. Bottom, Summary data
(n = 5) Error bars indicate SEM.
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Multisynaptic induction of hippocampal LTP with
theta-patterned stimulation
The selective induction of perforant path and mossy fiber LTP with
high- and low-frequency inputs, respectively, strongly suggests that
input signals incorporating induction parameters optimal for both
pathways will potentiate both populations of synapses. To test this
possibility, perforant path fibers were stimulated with high-frequency
"bursts" of impulses (each burst consisted of five pulses delivered
at 200 Hz), applied at a low frequency (interburst intervals of 100 msec), a pattern of activity observed in layer II of the entorhinal
cortex during behaviors associated with theta rhythm generation (Alonso
and Garcia-Austt, 1987), and shown previously to induce NMDA
receptor-dependent LTP maximally (Larson and Lynch, 1986; Rose and
Dunwiddie, 1986). The high frequency of activity within bursts is
optimal for LTP of the perforant path; the lower frequency
characterized by the interburst interval is optimal for LTP of mossy
fibers. Stimulating the perforant path with this theta-patterned input
(theta burst) resulted in the induction of LTP both
monosynaptically for perforant path input to dentate and
transsynaptically for mossy fiber input to CA3 (n = 5;
two-way repeated measures ANOVA, F = 67.393;
p < 0.001) (Fig. 10).
In additional experiments it was found that giving theta burst
stimulation at a lower intensity, or with fewer bursts (<20), could
result in monosynaptic LTP but not transsynaptic LTP. After
monosynaptic perforant path LTP, however, it was found that giving the
identical theta burst stimulation (previously subthreshold for
induction of transsynaptic LTP) could induce LTP transsynaptically for
mossy fiber input to CA3 (n = 4). LTP induced by theta
burst stimulation was NMDA receptor-dependent for perforant path input
but not for LTP of transsynaptic input to CA3, as assessed by the
application of D-APV (n = 2); this again
confirmed that transsynaptic LTP occurred via the mossy fiber
projection (Fig. 11).
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Figure 10.
Multisynaptic induction of hippocampal LTP with
theta-patterned stimulation. Schematic representation of the
hypothesized pattern of input to granule cells of the dentate gyrus and
CA3 pyramidal neurons using a stimulation pattern incorporating both high- and low-frequency impulses (200 Hz bursts of 5 impulses at 10 Hz;
50 bursts). Data show the consequences of theta-like patterns of
perforant path (pp) activation (theta
burst) on the induction of LTP (n = 5).
Error bars indicate SEM. LTP is induced both monosynaptically and
transsynaptically (i.e., multisynaptically) for perforant path input to
the dentate gyrus (monosynaptic LTP; top) and for mossy
fiber (mf) input to CA3 (transsynaptic LTP; bottom). Waveforms are averages of all responses evoked
in the last 5 min of a sample period. Calibration bars, 1 mV and 5 msec.
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Figure 11.
NMDA-independent induction of transsynaptic LTP.
Pressure ejection of the NMDA receptor antagonist D-APV
(100 µM; ~70 nl/min for 15-30 min) into the apical
dendrites of the CA3 and the dentate gyrus before theta burst
stimulation blocked the induction of perforant path
(pp) LTP (for both monosynaptic input to CA3 and the dentate) but not transsynaptic mossy fiber
(mf) LTP (waveforms are averages of responses
collected during last 5 min of a given sample period). Calibration
bars, 1 mV and 5 msec.
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| |
DISCUSSION |
In the studies reported here, we tested the hypothesis that
different patterns of activity within the same population of entorhinal cortical afferents could lead to a selective potentiation of spatially distinct populations of synapses within hippocampus, including those
activated transsynaptically. We focused specifically on potentiation of
direct, monosynaptic entorhinal input to dentate granule cells, which
expresses an NMDA receptor-dependent LTP, and on potentiation of
indirect, disynaptic entorhinal input to CA3 pyramidal cells, which is
transmitted by the mossy fiber projection of dentate granule cells and
expresses an NMDA receptor-independent LTP. The principal findings of
these experiments are as follows: (1) the stimulus prerequisites for
the induction of LTP differ for entorhinal afferents to the dentate
gyrus and mossy fiber afferents to CA3, such that higher stimulation
frequencies (>100 Hz) are more effective at inducing LTP of perforant
path input to granule cells of the dentate, and lower stimulation
frequencies (<100 Hz) induce monosynaptic mossy fiber LTP of CA3
pyramidal cells more efficiently; (2) consistent with the findings that propagation of activity through the trisynaptic pathway predominantly results from electrical stimulation of entorhinal afferents at 10-15
Hz, and that mossy fiber LTP can be induced with stimulation frequencies as low as 10 Hz, we found that low frequencies of activity
of entorhinal cortical axons (10-20 Hz) induces transsynaptic LTP of
dentate granule cell mossy fiber input to CA3 selectively; (3) patterns
of stimulation that mimic neuronal firing in the entorhinal cortex
during endogenous theta rhythm induce LTP both monosynaptically for
input to dentate granule cells and transsynaptically for mossy fiber
input to CA3; and (4) the ability to induce transsynaptic LTP of mossy
fiber input to CA3 with stimulation of entorhinal afferents using
either low-frequency or theta burst stimulation depends on the synaptic
strength of monosynaptic input to the dentate, such that LTP of
perforant path synapses increases the likelihood of transsynaptic
induction of mossy fiber LTP.
The results of these experiments show that in the intact
hippocampus, the constraints on perforant path and mossy fiber LTP induction imposed by differences at the cellular/molecular level interact with additional constraints imposed by other properties of the
network in which those synapses are embedded. Both perforant path and
mossy fiber synapses require a critical level of excitatory input from
the entorhinal cortex, either monosynaptically or transsynaptically. Although sharing this common requirement, it has been demonstrated previously, and confirmed here in vivo, that the
cellular/molecular mechanisms triggered when that critical level of
excitatory input is reached are different for the two populations of
synapses; perforant path LTP is NMDA receptor-dependent, whereas mossy
fiber LTP is not (Harris and Cotman, 1986; Wigstrom et al., 1986). The cellular/molecular differences underlying the induction of LTP for
these different subsets of synapses also may account for the differences in the optimal tetanization parameters necessary for inducing LTP. At lower frequencies of stimulation, LTP of perforant path input to the dentate was not induced because stimulation at 10-15
Hz does not result in sufficient depolarization to relieve the
Mg2+ block of NMDA channels (Blanpied and Berger,
1992). When the frequency of entorhinal input increases to  50-100
Hz, temporal summation of perforant path input increases sufficiently
for NMDA receptor activation and, thus, for the induction of LTP
(Collingridge et al., 1988). At the level of mossy fiber input to CA3,
frequencies of 50-100 Hz within the perforant path are not
efficiently transmitted transsynaptically, and as a result, the
induction of LTP is restricted to monosynaptically activated synapses.
Although entorhinal activity in the range of 10-15 Hz does not lead to
LTP of perforant path synapses, it does lead to frequency facilitation,
i.e., a progressive increase in the number of active granule cells
distributed over a wider spatial extent of the dentate gyrus. Because
of the high degree of convergence of granule cell projections onto CA3
pyramidal cells, the increased number of active granule cells leads to
greater levels of excitatory input sufficient to induce LTP of mossy
fiber synapses within CA3. Theta burst stimulation incorporates input parameters optimal for potentiation of both perforant path and mossy
fiber synapses, and as a result, LTP is induced monosynaptically and
transsynaptically. Thus, potentiation of perforant path and mossy fiber
synapses is achieved not only through two different mechanisms at the
cellular/molecular level but also through two different mechanisms at
the network level; the critical level of excitatory perforant path
input to granule cells is reached as a consequence of temporal
coincidence, whereas the critical level of mossy fiber excitation to
CA3 is reached as a consequence of spatial convergence.
More generally, the interaction between cellular/molecular
constraints and network constraints illustrated by these results provides an empirical basis for the possibility that the spatial distribution of potentiated synapses within a neural network varies dynamically as a function of the temporal properties of afferent activity. The relevance of this finding to hippocampal function is
based on the strong correspondence between the stimulation parameters
used here and the temporal characteristics of action potential activity
of hippocampal and entorhinal cortical neurons observed in the behaving
animal (Ranck, 1973; Berger et al., 1983). Further elaboration of this
basic principle may provide a basis for understanding several well
documented properties of hippocampal neuronal population activity that
evolve as a consequence of associative learning in the intact animal:
the nonuniform spatial distribution of hippocampal neurons expressing
learning-enhanced activity (i.e., "neural correlates") (O'Keefe,
1979; Berger et al., 1983; Eichenbaum et al., 1989), the dependence of
a particular spatial distribution of neural correlates on task
requirements and behavioral context (Christian and Deadwyler, 1986;
Wiener et al., 1989), and the functional importance of the
characteristic theta rhythmicity of hippocampal neural activity (Berry
and Thompson, 1978; Otto et al., 1991).
| |
FOOTNOTES |
Received Sept. 5, 1997; revised Oct. 21, 1997; accepted Oct. 23, 1997.
This work was supported by National Institute of Mental Health Grants
MH51722 and MH00343, the Human Frontiers Science Organization, and a
National Research Service Award fellowship to M.F.Y. We thank Christian
Perron for assistance with CSD analysis and Dr. Nicholas Poolos for a
critical reading of this manuscript.
Correspondence should be addressed to Dr. Mark F. Yeckel,
Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030. E-mail: myeckel{at}bcm.tmc.edu
| |
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Top
Abstract
Introduction
