Neuron, Vol. 18, 295–305, February, 1997, Copyright 1997 by Cell Press
Hippocampal Interneurons Express a Novel Form
of Synaptic Plasticity
Lori L. McMahon and Julie A. Kauer
Department of Neurobiology
Duke University Medical Center
Durham, North Carolina 27710
the equally important role of inhibitory interneurons in
modifying the behavior of hippocampal circuitry has re-
ceived little attention.
We have examinedsynaptic plasticity of stratum radi-
atum (s. radiatum)interneurons in the hippocampalCA1
region, which is the site of the most intensively studied
form of long-term potentiation (LTP). Excitatory affer-
ents from the CA3 region make en passant synapses
on multiplepyramidalcellsthat exhibit synapse-specific
(homosynaptic) LTP. The same CA3 afferents excite not
only pyramidalcellsbutalso theirinterneuron neighbors
in s. radiatum, which probably mediate the powerful
“feedforward” inhibition present in CA1 pyramidal cells
(Fox and Ranck, 1981; Alger and Nicoll, 1982; Buzsaki
and Eidelberg, 1982; Buzsaki, 1984; Ashwood et al.,
1984; Frotscher et al., 1984; Schwartzkroin and Kunkel,
Using visualized whole-cell patch-clamp recordings,
we find that the same stimulation that elicits LTP in
pyramidal cells markedly depresses excitatory syn-
apses onto CA1 interneurons in s. radiatum. We further
report that,unlikemost otherformsof synapticplasticity
in hippocampus, the long-lasting depression in in-
terneurons weakens not just active synapses but multi-
ple excitatory synapses onto the same interneuron. An
obvious consequenceof thisdepression willbe apotent
enhancement of the excitability of hundreds of pyrami-
dal cells normally innervated by each interneuron.
Individual GABAergic interneurons in hippocampus
can powerfullyinhibit morethana thousand excitatory
pyramidal neurons. Therefore, control of interneuron
excitability provides control over hippocampal net-
works. We have identified a novel mechanism in hip-
pocampus that weakens excitatory synapses onto
GABAergic interneurons. Following stimulation that
elicits long-term potentiation atneighboring synapses
onto excitatory cells, excitatory synapses onto inhibi-
tory interneurons undergo a long-term synaptic de-
pression (interneuron LTD; iLTD). Unlike most other
forms of hippocampal synaptic plasticity, iLTD is not
synapse specific: stimulation of an afferent pathway
triggersdepression notonly ofactivated synapsesbut
also of inactive excitatory synapses onto the same
afferent activity increases hippocampal excitability
through a dual mechanism, simultaneously potentiat-
ing synapses onto excitatory neurons and depressing
synapses onto inhibitory neurons.
of interneurons is limited compared with what is known
about excitatorypyramidalneurons.This situationarose
because interneurons are sparse and widely scattered,
making them unlikely targets for an electrode aimed
blindly at the brain slice (Figure 1A), and because in-
terneurons are notoriously difficult to record from for
longperiods usingsharpmicroelectrodes. Wehave suc-
cessfully used visualized whole-cell patch-clamp re-
cordings toovercome these problems (Sahet al., 1996).
To appreciate the functional role of s. radiatum in-
terneurons, the local circuit in which they participate
must be defined. These interneurons receive excitatory
afferent input from CA3 pyramidal cells and provide
feedforward inhibition to hundreds of CA1 pyramidal
cells (Figure 1B). The CA1 pyramids, inturn, send recur-
rent collaterals to innervate interneurons. The peak of
the EPSC recordedfrom an s. radiatum interneuron pre-
cedes the peak of the population pyramidal cell excit-
atory postsynaptic potential (EPSP) (Figure 1C), sug-
gesting that these interneurons are indeed activated
before CA1 pyramidal cells and provide feedforward
inhibition (latency from stimulus to field potential onset,
mean ? SEM: 3.9 ? 0.2 ms; latency to onset of in-
terneuron EPSC/EPSP: 2.8 ? 0.2 ms; n ? 23; p ? .003
by Student’s t test). In the experiments below, we have
focused exclusively on monosynaptic excitatory re-
sponses elicited by stimulation of CA3 afferents onto
The hippocampus contains a relatively small number of
inhibitory interneurons,whichcontrolthe outputof large
numbers of excitatory pyramidal neurons (Schwartz-
kroin and Mathers, 1978; Knowles and Schwartzkroin,
1981; Kawaguchi and Hama, 1987; 1988; Lacaille et al.,
1987; 1989; Lacaille and Schwartzkroin, 1988a; 1988b;
Sik et al., 1995). Interneurons have extensive axonal
arborsand innervatepyramidalcellsmultipletimes, sug-
gesting that each time an interneuron fires an action
potential, hundreds of postsynaptic cells will be reliably
and simultaneously inhibited (Schwartzkroin and Kun-
kel, 1985; Li et al., 1992; Buhl et al., 1994a; Cobb et al.,
1995;Siket al.,1995).Normalbrain function inthecortex
and hippocampus depends critically on the inhibitory
drive contributed by interneurons; for example, block-
adeofinhibition (viaGABAAreceptors) resultsinepilepti-
form activity (Wong and Prince, 1979; Wong and Traub,
ons may be involved in thegeneration and maintenance
of epilepsy, in which hippocampal excitatory neurons
become pathologically active and fire at high frequency
(Sloviter, 1987; 1991; 1992; Stelzer et al., 1987; Scharf-
man and Schwartzkroin, 1990; Zhao and Leung, 1991).
Surprisingly little is known about the control of in-
terneuron excitability; most analyses of inhibitory func-
tion have focused on the role of GABAergic inhibition
studied indirectly in excitatory neurons. Moreover, al-
ticity of excitatory synapses onto excitatory neurons,
Figure 1. (A) Distribution of interneurons in s. radiatum. The majority of s. radiatum interneurons express the calcium-binding protein,calbindin
(Freund et al., 1990; Toth and Freund, 1992); an anti-calbindin antibody was used to visualize the distribution of s. radiatum interneurons
within the slice preparation (1 cm ? 100 ?m).
(B) Diagram ofan s. radiatum interneuron inthe local circuit inarea CA1. Glutamatergic afferents from CA3 pyramidal cells(Schaffer collaterals)
synapse both onto the s. radiatum interneuron and onto dendrites of CA1 pyramidal cells. Stimulation of this pathway excites both cell types.
The GABAergic interneuron forms synapses onto pyramidal neurons, at either primarily somatic or primarily dendritic regions (Figure 5). CA1
pyramidal cells extend local excitatory collaterals that innervate interneurons.
(C) Stimulation of CA3 afferents elicits a field EPSP in CA1 pyramidal cells and a simultaneously recorded EPSC in a voltage-clamped
interneuron. The peak of the interneuron EPSC precedes the peak of the field EPSP, demonstrating that these interneurons are positioned
to participate in feedforward inhibition. The traces represent the average of 10 EPSCs and EPSPs.
Synaptic Plasticity in Hippocampal Interneurons
changes in voltage-dependent conductances in the
postsynaptic cellcould account forthe apparent synap-
tic depression observed in current-clamp recordings.
However,EPSC depressionwasalso observedinexper-
iments using voltage-clamp conditions, demonstrating
significantly to the synaptic depression (Figure 2B).
In experiments from 49 interneurons, excitatory neu-
rotransmission inthe majority was depressedafter teta-
nus (Figure 2C). EPSP/Cs were depressed in 32 cells,
unchanged in 14cells, and slightlypotentiated in 3 cells.
The depression occurred within 5 s after tetanus, and
posttetanic potentiation was generally not observed. In
9 of 32 cells, the EPSP/C returned to baseline levels
within 20 min. However, in the majority of interneurons
(23/32), synaptic depression persisted for the duration
of the recording (up to 70 min after tetanus). We refer
tothis formof synapticdepressionas “interneuronlong-
term depression” (iLTD).
Synapses onto Interneurons Undergo LTD When
Pyramidal Cell Synapses Undergo LTP
Thus, the same stimulus paradigm that produces LTP
in pyramidal cells produces iLTD in interneurons. To
demonstrate clearlythata 100Hztetanustriggers simul-
taneousLTP inCA1 pyramidalcellsand LTD ininterneu-
rons, we recorded from both cell types simultaneously.
We delivered a tetanus to CA3 afferents and recorded
both from an interneuron, using a patch electrode, and
from local pyramidal cells, using an extracellular re-
cording electrode (Figure 3A). While the tetanus trig-
gered LTP in the surrounding pyramidal cells, EPSP/Cs
in the majority of interneurons were again depressed
(13 of23cells) (Figure3B).Thus,incontrast tothesimple
expectation that all synapses of CA3 neurons will ex-
press LTP after tetanus, the same stimulus paradigm
that reliably produces LTP in pyramidal cells produces
iLTD in interneurons.
A second stimulus paradigm that is very effective at
triggering pyramidal cell LTP is known as “pairing”: low
frequency stimulation of afferent fibers is paired with
and produce LTP (Kelso et al., 1986; Gustafsson et al.,
1987; Kauer et al., 1988). To further explore the nature
of iLTD, we used the pairing protocol with interneurons.
Depolarization of interneurons “paired” with 60 presyn-
aptic stimuli at 1 Hz failed to change the strength of
excitatory inputs onto interneurons (Figure 3C), sug-
gesting that the requirements to initiate pyramidal cell
LTP differ from those required to initiate iLTD (EPSP
slope 5 min postpairing: 103% ? 5% of control; n ? 13).
Subsequent tetanic stimulation triggered iLTD (EPSP
slope 5 min posttetanus: 85% ? 8%; n ? 9). In support
of the idea that iLTD is distinct from LTP, iLTD was
still observed even when voltage-clamped interneurons
received tetanus without concomitant postsynaptic de-
polarization (n ? 3), a condition that reduces or blocks
LTP induction in pyramidal cells (Malinow and Miller,
1986; Kelso et al., 1986).
Figure 2. iLTD Is Induced After High Frequency Stimulation of CA3
(A) Current-clamp recording from an interneuron before and after
100 Hz tetanus (arrow). Example traces (inset) are taken from por-
tions of the time course marked A (control) and B (after tetanus). In
thisexample and others, eachpoint representsthe average of three
EPSPs. Calibration: 10 mV, 10 ms.
(B) Voltage-clamp recording from an interneuron before and after
100Hz tetanus (arrow).Example traces (inset) are takenat the times
marked A(control) andB (after tetanus). The right-hand inset shows
the“aftertetanus” EPSCscaledto matchcontrol amplitude.Calibra-
tion: 100 pA, 10 ms.
(C) Summary data from 49 interneurons receiving tetanus at the
arrow. Experiments recording from interneurons in voltage clamp
(n ? 20) and current clamp (n ? 29) are pooled in this figure. All
experimentsare included regardlessof whether iLTDwas observed.
Error bars in this figure and all others represent the mean ? SEM.
High Frequency Stimulation Elicits LTD
Brief high frequency stimulation of CA3 afferents trig-
gers LTP at excitatory synapses onto CA1 pyramidal
cells (Andersen et al., 1973; Alger and Teyler, 1976). We
began by examining the effects of stimulating the same
afferents onto neighboring interneuron synapses, spe-
cifically asking if they are enhanced like synapses onto
pyramidal cells. We thereforerecordedEPSPs ins. radi-
atum interneurons before and after tetanic stimulation
of presynaptic Schaffer collateral axons (100 Hz for 1 s).
In sharp contrast to the synaptic potentiation that this
stimulation evokes in pyramidal cells, EPSPs in in-
terneurons were markedly reduced in amplitude imme-
diately after tetanic stimuli (Figure 2A). In theory,
Interneuron LTD Is Not Synapse Specific
Excitatory synapses onto pyramidal cells undergo LTP
in response to tetanic stimulation, but after prolonged
lower frequency stimulation (e.g., 1 Hz) also express
LTD(Dudek andBear, 1992;Mulkey and Malenka,1992).
LTP and LTD in pyramidal cells are homosynaptic: only
activated synapses are enhanced or depressed, while
inactive synapses remain unaffected (Andersen et al.,
1977; 1980; Lynch et al., 1977; Dudek and Bear, 1992;
Mulkey and Malenka, 1992).
Because synaptic plasticity in pyramidal cells is ho-
mosynaptic, we were interested in determining whether
iLTD is similar. To test this idea directly, we recorded
from an interneuron while alternately stimulating two
independent excitatory synaptic inputs onto the cell.
Tetanic stimulationwas delivered to only one of the two
afferent pathways, while the result was monitored in
both (Figure 4A and 4B). After tetanus to one input,
EPSCs in both pathways were immediately depressed.
Similar results were observed ineight interneurons (Fig-
ure 4C). This result strongly argues that high frequency
stimulation of one set of synapses depresses other,
unstimulated excitatory synapses on the same in-
Consistent with this idea, the late EPSP/C, which
clearly arises from synapses that differ from those re-
ceiving tetanic stimulation (most likely from recurrent
collaterals of CA1 neurons, see Figure 4D), was often
depressed along with the monosynaptic EPSP/C. Since
theCA3–CA1 pyramidalcellsynapse ispotentiated after
tetanus, we expected the late recurrent EPSP/C in the
interneurons toreflect this by potentiatingas well(Mac-
caferriand McBain,1995).Althoughthiswas observedin
some cases(10 of 23cells with an obviouslate EPSP/C)
(Figure 4D, bottom), in other interneurons, late polysyn-
aptic events were depressed (13 of 23 cells) (Figure
4D, top). These data support the idea that iLTD is not
synapse specific, triggering depression at multiple ex-
citatory synapses onto the interneuron following high
frequency stimulation of a single set of synapses. Thus,
iLTD differs fundamentally from pyramidal cell LTP
Interneurons That Undergo iLTD Do Not Form
a Homogeneous Anatomical Class
Hippocampal interneurons are more heterogeneous
than their pyramidal cell neighbors, varying in axon ter-
minal fields, dendritic arrangement, and expression of
neuropeptides and Ca2?-binding proteins (Lorente de
No, 1934; Schwartzkroin and Kunkel, 1985; Sloviter and
Nilaver, 1987; Babbet al., 1988;Freund et al.,1990; Buhl
et al., 1994b; McBain et al., 1994; Sik et al., 1995). To
predict the effects of iLTD on local circuitry more thor-
oughly, each interneuron from which we recorded was
Figure 3. Tetanus Simultaneously Elicits iLTD in Interneurons and
LTP in CA1 Pyramidal Cells
(A) Typical experiment illustrating that an interneuron recorded un-
der current clamp shows synaptic depression immediately after
tetanus (top graph), while neighboring CA1 pyramidal cells respond
to the same tetanus with LTP (bottom graph). Top inset shows the
interneuron EPSP and response to a hyperpolarizing current step
before and 20 min after tetanus. The EPSP is depressed while the
cell input resistanceisunchanged. Bottom inset showsextracellular
15 mV, 20 ms; bottom graph, 0.5 mV, 10 ms.
(B) Summary graph of experiments recording either simultaneous
intra- and extracellular recordings from pyramidal cells (open cir-
cles, n ? 13) or simultaneous intracellular recordings from interneu-
rons and extracellular recordings from pyramidal cells (closed cir-
cles, n ? 23). Tetanus was delivered at the arrows. The top graph
compares intracellularly recorded pyramidal cell potentiation with
interneuron depression, while the bottom graph demonstrates that
in both sets of experiments, field EPSPs were equally potentiated.
(C) Pairing synaptic stimulation with postsynaptic depolarization
does not induce iLTD. An interneuron was depolarized to ?10 mV
and stimulated 60 times at 1 Hz. When the membrane was repolar-
ized, synaptic depression was not observed. Subsequent tetanic
stimulation, however, triggered iLTD. Example traces (inset) illus-
trate EPSPs taken at the times denoted by A (control), B (after
pairing), and C (20 min after tetanus). Calibration: 20 mV, 20 ms.
Synaptic Plasticity in Hippocampal Interneurons
Figure 4. iLTD Is Not Synapse Specific
(A) Example of iLTD elicited by tetanus to a
EPSCsina second, independentpathway re-
corded in an interneuron. Path 1 received te-
tanic stimulation at the arrow and exhibited
LTD; path 2 was not stimulated at the arrow
yetshowed cleariLTD after tetanus to path 1.
(B) EPSCs taken from the experiment in (A).
The top traces illustrate the iLTD observed in
responsesfrom path 1 (left) andpath 2 (right).
In the bottom traces, the depressed EPSC
has been scaled to match the control ampli-
tude. Calibration: 200 pA, 10 ms.
(C) Summary graph of eight experiments in
which one of two independent pathways re-
ceived tetanic stimulation. The top graph
shows the mean responses in the pathway
receiving tetanus, and the bottom graph
shows the mean responses in the control,
four were carried out under voltage-clamp
and four under current-clamp conditions.
(D) Right lane: examples of EPSPs from two
different interneurons. The initial EPSP re-
flects the monosynaptic input from CA3,
while the late EPSPs may result from activa-
tionof recurrent collaterals from CA1 pyrami-
dal cells (see circuit diagram). In each pair of
traces, thethin line representscontrol EPSPs
while the thick line represents EPSPs follow-
ing tetanus. Although the monosynaptic
EPSPis depressed ineach of these cells,the
late EPSP in one is depressed (top traces),
while in the other it is enhanced (bottom
traces). Calibration: 20 mV, 20 ms.
filled with biocytin, fixed, and reconstructed. Of 49 in-
terneurons, 30 filled well enough to identify axon termi-
nation fields. Dendrites branched only sparsely and
were aspiny. Cells typically had one of two distinct pat-
terns of axonal arbor: either heavy innervation close to
and within s. pyramidale, (basket cells, right-hand cell
in Figure 5) or axonal branching throughout s. radiatum
and s. oriens (bistratified cells, left-hand cell in Figure
5). The basket cells are likely to inhibit action potential
generation at the cell body, while the bistratified cells
Figure 5. Morphological Features of s. radiatum Interneurons
Camera lucida drawings of the two major classes of interneurons in s. radiatum, as defined by axonal projections. Left: bistratified cell, with
axon throughout s. radiatum and s. oriens. Right: basket cell, with axon primarily in s. pyramidale. Scale bar ? 100 ?m.
appear specialized to deliver inhibition to the dendrites,
interacting there with excitatory synapses. The axon
dale and left the plane of each 400 ?m thick slice at
both edges, suggesting that our measurements under-
estimate the true termination zone. These extensive
axon arborizations support the idea that a single in-
terneuron simultaneouslyinhibits hundredsofpyramidal
cells, functionally grouping and synchronizing local ex-
Of 49 s. radiatum interneurons, 32 (65%) responded
to tetanus with LTD. We hypothesizedthat perhaps one
functional type of interneuron might express iLTD while
the other might not. However, the ability to undergo
iLTD isnotcorrelated withthetwomorphologicallyiden-
tified cell types present in ourmaterial, based onaxonal
arborization: of 19 cells with identifiable axons that ex-
hibited synaptic depression, 8 were bistratified cells,
with axons ins. radiatum/s. oriens,while 11werebasket
cells, with axons primarily innervating s. pyramidale.
Therefore, each of the major interneuron types in s.
radiatum can undergo synaptic depression after high
both major anatomical classes (based on axonal mor-
phology) exhibit iLTD.
Interneuron LTD May Explain
Indirect evidence from previous studies supports the
idea that inhibitory circuits are depressed following
stimulation that triggers LTP in pyramidal cells. In area
CA3, following 20 Hzstimulation of excitatory afferents,
previously unseen synaptic connections between pyra-
midal cells become apparent (Miles and Wong, 1987).
This observation was attributed to reduced GABAergic
inhibition that revealed “latent” excitatory connections.
This result can be explained if significant iLTD follows
20 Hz stimulation.
A large body of literature has reported a form of en-
hancement termed EPSP–spike potentiation (E–S po-
tentiation), both in area CA1 and in the dentate gyrus
(Bliss and Lomo, 1973; Andersen et al., 1980; Wilson,
1981; Wilson et al., 1981; Abraham et al., 1985; 1987;
Taube and Schwartzkroin, 1988; Chavez-Noriega et al.,
1990; Tomasuloet al., 1991).High frequency stimulation
not only triggers synapticpotentiation inpyramidal cells
(LTP) but also reduces the threshold for action potential
generation, such that an EPSP of a given size produces
action potentials more easily. As GABAAantagonists
strongly reduce E–S potentiation, at least part of the
increased excitability results from disinhibition (Abra-
ham et al.,1987; Tomasulo et al.,1991; butsee Aszetely
and Gustafsson, 1994). This finding suggests that excit-
or are depressed following tetanic stimulation. iLTD al-
most certainly contributes to E–S potentiation, since
following a tetanus, an excitatory input onto an in-
terneuron will produce a smaller EPSC and a smaller
downstream release of GABA onto GABAA receptors
that normally control spike threshold in local pyramidal
High frequency stimulation of excitatory CA3 afferents
results ina persistentdepressionofexcitatory synapses
onto interneurons. iLTD is triggered by the same stimu-
lus pattern that causes neighboringexcitatory synapses
onto pyramidal cells to undergo LTP. Unlike LTP or LTD
in excitatory hippocampal cells, iLTD is not synapse
specific, as both mono- and polysynaptic excitatory in-
puts onto interneurons aredepressedafter tetanus, and
tetanic stimulation delivered toone set of afferents pro-
duces concomitant depression in an independent set
of afferents onto the same interneuron. Interneurons of
Synaptic Plasticity in Hippocampal Interneurons
Synaptic Plasticity at Excitatory Synapses
on Other Hippocampal Interneurons
Synaptic plasticity has been examined in other in-
terneurons of the hippocampus. Following high fre-
quency stimulation, excitatory responses in some in-
terneurons have been reported to potentiate, some to
depress, and some to remain unchanged (Buzsaki and
synaptic plasticity with interneuron type or function.
More recently,a pairing protocol wasreported toinduce
LTP in one class of s. radiatum nonpyramidal cell that
was morphologically distinct from the s. radiatum in-
terneurons in which we have observed iLTD; consistent
with our observations, interneurons with morphologies
like our cells always failed to exhibit LTP (Maccaferri
and McBain, 1996). LTP at interneurons in a different
stratum of CA1 (s. oriens) has been reported following
tetanus (Ouardouz and Lacaille, 1995). It appears, how-
ever, that the potentiated synapse is onpyramidal cells,
which in turn provide a larger recurrent EPSC to the
interneuron; themonosynaptic EPSC from CA3neurons
does not support LTP (Maccaferri and McBain, 1995;
1996). Taken together, these experiments support the
idea that the majority of excitatory synapses on hippo-
campal interneurons do not exhibit LTP.
The latter three studies were carried out at roomtem-
perature; one reason for the apparent absence of iLTD
may be the temperature sensitivity of the phenomenon.
In pilot studies for the present work, we found little or
ments were carried out at 22?C (L. L. M. and J. A. K.,
1995, Soc. Neurosci., abstract 20, p. 847). Increasing
the temperature to 30?C markedly increased the num-
ber of experiments yielding synaptic depression, sug-
gesting that the underlying mechanism of iLTD may be
iLTD is clearly different than the “passively propa-
gated” LTDobservedins. oriensinterneurons.The plas-
ticity in this system occurs only at excitatory synapses
onto pyramidal cells; these are then less effective at
exciting interneurons via recurrent axon collaterals
(Maccaferri and McBain, 1995). In our interneurons, the
same stimulus that triggers potentiation in surrounding
pyramidal cells clearly induces iLTD in s. radiatum in-
terneurons. Recurrent collaterals from CA1 pyramidal
cells are unlikely to contribute to the monosynaptic
EPSC measured in the present work, since the EPSC
peak precedesthepeak of thepyramidal cellpopulation
EPSP. In fact, our data suggest that multiple excitatory
synapses on a given interneuron are depressed after
high frequency afferent stimulation, so that not only
feedforward inhibition but also feedback inhibition can
be affected by iLTD.
cerebellar Purkinje cells (Ito et al., 1982; Linden et al.,
1991). However, unlike LTD in these neurons, iLTD is
not synapse specific, so that independent pathways
onto thesame interneuron aredepressedfollowing teta-
nus to just one pathway. A similar heterosynaptic de-
pression has also been reported following tetanus to
glutamatergic afferents in the neostriatum (Calabresi et
al., 1992; Lovinger et al., 1993). The fact that iLTD is not
synapse specific argues strongly that the locus of iLTD
is not presynaptic, since it is difficult to imagine how
one population of presynaptic fibers could communi-
cate with an entirely separate, spatially distant popula-
tion of presynapticfibers.In addition,Ca2?entrythrough
NMDA channels is not sufficient to trigger iLTD, as in-
terneuron LTD is not triggered after pairing membrane
depolarization with afferent stimulation (a protocol that
triggers robust LTP in pyramidal cells by maximizing
and McBain, 1996). In support of this, voltage clamping
the neuron at negative potentials that minimize NMDA
currents does not prevent iLTD.
A second possible explanation of our results is that
tetanic stimulation produces an extracellularly released
factor that triggers LTD. Recent evidence suggests that
strong tetanic stimulation of s. radiatum can produce
synaptic depression in unstimulated pathways onto py-
(Christie et al., 1994; Barr et al., 1995; Scanziani et al.,
1996) and apparently requires activity incells other than
al. (1996) suggest that a soluble factor may be released
extracellularly, causing nonspecific depressionof gluta-
matergic transmission at local synapses. We currently
favor the idea that this factor may also be responsible
for the iLTD at interneuron synapses.
iLTD Contribution to the Development
of Epileptiform Electrical Activity
We have identified a novel mechanism in hippocampus
that weakens excitatory synapses onto GABAergic in-
terneurons. Since interneurons control and synchronize
theoutput oflargegroupsofpyramidal cells,depression
of multiple excitatory synapses onto an interneuron will
disinhibit many pyramidal cells and disrupt function.
Although we cannot sayas yetunder what physiological
conditions iLTD is elicited, it is clearly observed after
high frequency firing of afferents like that seen during
epileptiform activityand islikely to contribute toor even
underlie hippocampaldisinhibition duringepilepsy. One
possibility might be that high frequency afferent activity
allows a large Ca2?influx through Ca2?-permeable
AMPA channels, present on at least some hippocampal
interneurons (McBain and Dingledine, 1993).
iLTD may represent an earlyform of thedormant bas-
ket cell phenomenon, observed in animal models of epi-
lepsy (Sloviter, 1991). Although dormant basket cells
(interneurons) in epileptic tissue remain viable and can
release GABA, they are functionally denervated or “dor-
mant” (Sloviter, 1987; 1991). Disinhibition in dentate
granule cells follows either kainic acid treatment (re-
sulting in seizures) (Sloviter, 1992) or high frequency
electrical stimulation (Stelzer et al., 1987; Scharfman
and Schwartzkroin, 1990; Zhao and Leung, 1991), each
Mechanism of iLTD Is Distinct from That
for Pyramidal Cell LTP or LTD
Two distinct mechanisms could account for iLTD. First,
interneuron synapsesmaybedepresseddue totheacti-
vation of intracellular processes in the postsynaptic in-
terneuron, like LTD in hippocampal pyramidal cells (Du-
dek and Bear, 1992; Mulkey and Malenka, 1992) or in
Figure 6. Diagram Illustrating the Consequences of iLTD on the Local Circuit in the CA1 Region
Interneurons of s. radiatum innervate CA1 pyramidal cells, releasing GABA either onto cell bodies or onto dendrites (not illustrated). Darker
shading of the pyramidal cell represents hyperpolarization, while lighter shading represents depolarization.
(A) Excitatory afferents from CA3 release glutamate onto pyramidal cells and interneurons.
(B) After high frequency stimulation, LTP is induced at some pyramidal cell synapses, but synapses on interneurons undergo LTD, making
interneurons far less excitable, resulting in less GABA released onto their pyramidal cell targets. Through these complimentary mechanisms,
CA1 pyramidal cells become more excitable than before high frequency afferent activity.
was replaced by 4 mM MgCl2, and 100 ?M picrotoxin was included;
the bath temperature was maintained at 29–31?C. The CA3 region
of the slice was removed using a scalpel cut to prevent epileptiform
Tight-seal whole-cell recordings were obtained from thecell bod-
ies of interneurons located in s. radiatum or from pyramidal cells in
the CA1 region (McBain et al., 1994). Patch electrodes were pulled
from borosilicate glass and had resistances of 2–5 M? when filled
with (mM): potassium gluconate, 100; EGTA, 0.6; Na–GTP, 0.3; Na–
ATP, 2; MgCl2, 5; HEPES, 40; and biocytin, 0.4%. For voltage-clamp
recordings, 100 mM cesium gluconate was substituted for potas-
siumgluconate. Thepatch pipet waspositioned under visualcontrol
within s. radiatum using a Zeiss water immersion 40 ? objective
withHoffman-modifiedoptics. Recordingsweremadeusing anAxo-
patch200or anAxoclamp 2A,and cellswereeithervoltageclamped
to ?85 mV or held at ?85 mV in bridge mode by passage of current
into the electrode. Input resistance ranged from 200–700 Mohms,
and series resistance ranged from 10–30 Mohms. Input resistance
and series resistance were carefully monitored on-line, and experi-
ments werediscardedifchanges ?10% wereseen. Fieldextracellu-
lar recordings were made by placing a microelectrode (?1 M?)
filled with 2 M NaCl into s. radiatum close to the interneuron and
approximately “on-beam” with the stimulating electrode.
Records were filtered at 1–2 kHz and digitized at 5–10 kHz on an
80486 personal computer using software written in the Axobasic
programming environment and kindly donatedby Drs. Daniel Madi-
son and Felix Schweizer. The maximal initial slope of field EPSPs
and intracellularly recorded EPSPs, and the peak amplitudes of
voltage-clamped EPSCs were measured. No differences in iLTD
were observed between current-clamp and voltage-clamp re-
cordings, and data using each recording mode have been pooled
in the figures, using the percent change in EPSP slope and the
percentchangeinEPSCamplitude (since EPSCamplitude isdirectly
proportional to slope). Baseline values were defined as the mean
value of the EPSC amplitude or EPSPslope during the 2 minperiod,
3 min prior to tetanus.
of which produces patterns of hippocampal sclerosis
resembling that seen in human temporal lobe epilepsy
(Bruton, 1988). The original dormant basketcell hypoth-
esis included the idea that presynaptic excitatory cells
simply die in epilepsy, leaving a normal inhibitory cell
without innervation (Franck et al., 1988; Sloviter, 1991;
Nakajima et al., 1991). Other data suggest instead that
interneurons becomelessexcitableafterhigh frequency
stimulation or after kainate lesionsof CA3 (Franck et al.,
1988; Scharfman and Schwartzkroin, 1990; Nakajima et
al., 1991). Our results show directly that interneuron re-
sponsiveness is decreased within seconds after high
frequency stimulation without death of afferents. iLTD
may thus produce functional denervation of hippocam-
pal interneurons as a consequence of epileptiform
Because feedforward interneurons innervate hundreds
of pyramidal cells, induction of iLTD in a single in-
terneuron will increase the excitability of large groups
local inhibition, excitatory synapses on pyramidal cells
that have been potentiated will be more effective at
driving CA1 pyramidal cells to threshold, powerfully en-
hancing excitation in the local region.
Recordings and Analysis
Sprague–Dawley rats (16–26 days old) were decapitated following
deep halothane anesthesia. The brain was rapidly removed and
placed in ice-cold ACSF (mM): NaCl, 119; NaHCO3, 26; KCl, 2.5;
NaH2PO4, 1; CaCl2, 2.5; MgSO4, 1.3; and glucose, 10; saturated with
95% O2and 5% CO2(pH 7.4). Coronal slices (400 ?m) were cut
immediately from the dorsal hippocampus using a vibratome. After
cutting, slices were held for 1–5 hr in an interface chamber at room
temperature and transferredto a recording chamber wherethe slice
was heldsubmerged between two nets.The recording solution was
identical to ACSF except that CaCl2was increased to 4 mM,MgSO4
Abipolar stimulating electrode was placed ins. radiatum to activate
Shaffer collaterals of the CA3 pyramidal cells at 0.2 Hz. The evoked
EPSC or EPSP often included late polysynaptic events that likely
result from CA1 recurrent collaterals excited by CA3 afferents (Fig-
ures 1B and 4D); only the early monosynaptic event was measured
(see Figure 1C). Monosynaptic events in the presence of picrotoxin
Synaptic Plasticity in Hippocampal Interneurons
were entirely abolished in CNQX and d,l-APV, demonstrating that
they result from activation of glutamatergic fibers (unpublished
data). The latency to onset of EPSPs and EPSCs was measured by
hand from the center of the stimulus artifact to the event onset.
Reported values are the means ? the SEM. Latencies for EPSCs in
voltage-clamp experiments ranged from 1.2–5.3 ms; corresponding
fieldpotentialonsets ranged from2.7–6.5ms.Latenciesfor EPSPsin
current-clamp experiments ranged from 1.4–4.3 ms; corresponding
field potential onsets ranged from 2.3–5.6 ms.
After a stable baseline period of 7–20 min, afferents were stimu-
lated twice at 100 Hz for 1 s with a 20 s interval between trains;
the intensity was increased 1.5-fold during tetanic stimulation. We
routinely depolarized the neuron during tetanic stimulation when
the experiment was carried out in voltage clamp, to permit the
membrane to depolarize during the tetanus. “Pairing” was achieved
by depolarizing the cell to approximately ?10 mV during 60 afferent
stimuli at test intensity at 1 Hz. Of 13 pairing experiments, 4 were
carriedout usingtheperforatedpatchtechnique(0.25?g/ml ampho-
tericin added to potassium gluconate internal solution). The general
health of the interneuron did not change after pairing or tetanus, as
assessed by measurements of input resistance andaction potential
To stimulate two afferent pathways, a second stimulating elec-
trode was placed on the side of the interneuron opposite that of
thefirst stimulatingelectrode. The averagedistance between stimu-
lating electrodes as measured post hoc in fixed slices was 850 ?m.
Independence was assessed by testing for paired-pulse facilitation
between the two pathways (interpulse interval, 30 ms).
in rat hippocampal pyramidal cells studied in vitro. J. Physiol. 328,
Andersen, P., Teyler, T., andWester, K. (1973). Long-lasting change
in synaptic transmission in a specialized cortical pathway. Acta
Physiol. Scand. Suppl. 396, 34.
Andersen, P., Sundberg, S.H., Sveen, O., and Wigstrom, H. (1977).
Specific long-lasting potentiation of synaptictransmission in hippo-
campal slices. Nature 266, 736–737.
Andersen, P., Sundberg, S.H., Sveen, O., Swann, J.W., and Wigs-
trom, H. (1980). Possible mechanisms for long-lasting potentiation
of synaptic transmission in hippocampal slices from guinea pigs. J.
Physiol. 302, 463–482.
Ashwood, T.J., Lancaster, B., and Wheal, H.V. (1984). In vivo and
in vitro studies on putative interneurones in the rat hippocampus:
possible mediators of feed-forward inhibition. Brain Res. 293,
Aszetely, F., and Gustafsson, B. (1994). Dissociation between long-
term potentiation and associated changes in field EPSP waveform
in thehippocampal CA1 region: an in vitro study in guinea pig brain
slices. Hippocampus 4, 148–156.
Babb, T.L., Pretorius, J.K., Kupfer, W.R., and Brown, W.J. (1988).
Distribution of glutamate-decarboxylase-immunoreactive neurons
microscopy. J. Comp. Neurol. 278, 121–138.
Barr, D.S., Lambert, N.A., Hoyt, K.L., Moore, S.D., Wilson, W.A.
(1995). Inductionand reversal of long-term potentiation by low- and
high-intensity theta pattern stimulation. J. Neurosci. 15, 5402–5410.
Bliss, T.V.P., and Lomo, T. (1973). Long-lasting potentiation of syn-
aptic transmission in the dentate area of the anaesthetized rabbit
following stimulation of theperforant path. J. Physiol.232, 331–356.
Bruton, C.J.(1988).The Neuropathology ofTemporal Lobe Epilepsy.
(New York: Oxford University Press).
Buhl, E.H., Halasy, K., and Somogyi, P. (1994a). Diverse sources
of hippocampal unitary inhibitory postsynaptic potentials and the
number of synaptic release sites. Nature 368, 823–828.
Buhl, E.H., Han, Z.-S., Lo ¨rinczi, Z., Stezhka, V.V., and Somogyi, P.
(1994b). Physiological properties of anatomically identified axo–
axonic cellsintherathippocampus. J.Neurophysiol. 71,1289–1307.
Buzsaki, G. (1984). Feed-forward inhibition in the hippocampal for-
mation. Prog. Neurobiol. 22, 131–153.
Buzsaki, G., and Eidelberg, E. (1982). Direct afferent excitation and
long-term potentiation of hippocampal interneurons. J. Neurophys-
iol. 48, 597–607.
Calabresi, P., Maj, R., Pisani, A., Mercuri, N.B., and Bernardi, G.
(1992). Long-termsynaptic depressionin thestriatum: physiological
and pharmacological characterization. J. Neurosci. 12, 4224–4233.
Chavez-Noriega, L.E., Halliwell, J.V., and Bliss, T.V.P. (1990). A de-
crease infiringthreshold observedafterinductionof theEPSP–spike
(E–S) component of long-term potentiation in rat hippocampal
slices. Exp. Brain Res. 79, 633–641.
Christie, B.R., Kerr, D.S., and Abraham, W.C. (1994). Flip side of
synaptic plasticity: long-term depression mechanismsin the hippo-
campus. Hippocampus 4, 127–135.
Cobb, S.R., Buhl, E.H., Halasy, K., Paulsen, O., and Somogyi, P.
(1995). Synchronization of neuronal activity inhippocampus by indi-
vidual GABAergic interneurons. Nature 378, 75–78.
Dudek, S.M., and Bear, M.F. (1992). Homosynaptic long-term de-
pression in area CA1 of hippocampus and effects of N-methyl-D-
aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89, 4363–
istics of hippocampal complex–spike cells and theta cells. Exp.
Brain Res. 41, 399–410.
Franck, J.E., Kunkel, D.D., Baskin, D.G., and Schwartzkroin, P.A.
(1988). Inhibition in kainate-lesioned hyperexcitable hippocampi:
physiologic, autoradiographic, and immunocytochemical observa-
tions. J. Neurosci. 8, 1991–2002.
Freund, T.F., Gulyas, A.I., Acsady, L., Gorcs, T., and Toth, K. (1990).
Immediately after use, slices were fixed in 4% paraformaldehyde
and resectioned at 75 ?m. The sections were reacted as described
with avidin–horseradish peroxidase (McBain et al., 1994). Sections
were mounted on slides, and camera lucida drawings were made,
collapsing the three-dimensional morphology into a line drawing in
After a 1 hr rest period, freshly cut hippocampal slices were fixed
overnight in 4% paraformaldehyde. Fixed slices were incubated in
0.2 M glycine followed by 30% sucrose and serially resectioned at
30 ?m. Slices were then preincubated for 2 hr in 3% normal goat
serum with triton-X and overnight in primary rabbit anti-calbindin
antibody (1:500;) at 4?C. Following this, the slices were incubated
(for 1 hr) in a secondary donkey anti-rabbit antibody (1:100) conju-
gated to rhodaminefor visualization. Antibodies wereobtained from
The authors thank Scott Douglas for histological and immunocyto-
chemical staining of interneurons, and Drs. Lawrence Katz, Donald
Lo, Felix Schweizer, and John H. Williams for helpful comments on
the manuscript. This work was supported by NIH grants NS30500
to J. A. K. and NRSA NS09734 to L. L. M.
Received July 26, 1996; revised December 24, 1996.
Abraham, W.C., Bliss, T.V.P., and Goddard, G.V. (1985). Hetero-
synaptic changes accompany long-term but not short-term potenti-
ation of the perforant path in the anaesthetized rat. J. Physiol. 363,
Abraham, W.C., Gustafsson, B., and Wigstrom, H. (1987). Long-
term potentiation involves enhanced synaptic excitation relative to
synaptic inhibition in guinea-pig hippocampus. J. Physiol. 394,
ity in the CA1, CA3, and dentate regions of the rat hippocampal
slice. Brain Res. 110, 463–480.
Alger, B.E., andNicoll, R.A. (1982).Feed-forward dendritic inhibition
Serotonergic control of the hippocampus via local inhibitory in-
terneurons. Proc. Natl. Acad. Sci. USA 87, 8501–8505.
Frotscher, M., Leranth, C.S., Lubbers, K., and Oertel, W.H. (1984).
Commissuralafferents innervateglutamatedecarboxylase immuno-
reactive non-pyramidal neurons in the guinea pig hippocampus.
Neurosci. Lett. 46, 137–143.
Gustafsson, B., Wigstrom, H., Abraham, W.C., and Huang, Y.-Y.
(1987). Long-term potentiation in the hippocampus using depolariz-
ing current pulses as the conditioning stimulus to single volley syn-
aptic potentials. J. Neurosci. 7, 774–780.
Ito, M.,Sakurai, M., andTongroach,P. (1982).Climbing fibreinduced
depression of both mossy fibre responsivenessand glutamate sen-
sitivity of cerebellar Purkinje cells. J. Physiol. 324, 113–134.
Kauer, J.A.,Malenka, R.C.,andNicoll, R.A. (1988).Apersistent post-
synaptic modification mediates long-term potentiation inthe hippo-
campus. Neuron 1, 911–917.
Kawaguchi, Y., andHama,K. (1987).Twosubtypes ofnon-pyramidal
cells in rat hippocampal formation identified by intracellular re-
cording and HRP injection. Brain Res. 411, 190–195.
Kawaguchi, Y., and Hama, K. (1988). Physiological heterogeneity of
nonpyramidal cells in rat hippocampal CA1 region. Exp. Brain Res.
Kelso, S.R., Ganong, A.H., and Brown, T.H. (1986). Hebbian syn-
apses in hippocampus. Proc. Natl. Acad. Sci. USA 83, 5326–5330.
Knowles, W.D., and Schwartzkroin, P.A. (1981). Local circuit synap-
tic interactions in hippocampal brainslices. J. Neurosci. 1, 317–322.
Lacaille, J.-C.,andSchwartzkroin, P.A.(1988a).Stratum lacunosum–
moleculare interneurons of hippocampal CA1 region. I. Intracellular
response characteristics, synaptic responses, and morphology. J.
Neurosci. 8, 1400–1410.
Lacaille, J.-C., and Schwartzkroin, P.A. (1988b). Stratum lacuno-
sum–moleculare interneurons of hippocampal CA1 region. II. Intra-
somatic and intradendritic recordings of local circuit synaptic inter-
actions. J. Neurosci. 8, 1411–1424.
Lacaille, J.-C., Mueller, A.L., Kunkel, D.D., and Schwartzkroin, P.A.
(1987).Local circuitinteractionsbetween oriens/alveusinterneurons
and CA1 pyramidal cells in hippocampal slices: electrophysiology
and morphology. J. Neurosci. 7, 1979–1993.
Lacaille, J.-C., Kunkel,D.D., andSchwartzkroin, P.A.(1989).Electro-
physiological and morphological characterization of hippocampal
interneurons. In: The Hippocampus–New Vistas. (New York: Alan R.
Liss, Inc.), pp. 287–305.
Li, X.-G., Somogyi, P., Tepper, J.M., and Buzsaki, G. (1992). Axonal
and dendritic arborization of an intracellularly labeled chandelier
cell in the CA1 region of rat hippocampus. Exp. Brain Res. 90,
Linden, D.J., Dickinson, M.H., Smeyne, M., and Connor, J.A. (1991).
A long-term depression of AMPA currents in cultured cerebellar
Purkinje neurons. Neuron 7, 81–89.
Lorente de No, R. (1934). Studies on the structure of the cerebral
cortex. II. Continuation of the study of the Ammonic system. J.
Psychol. Neurol. 46, 113–177.
Lovinger, D.M., Tyler, E.C., and Merritt, A. (1993). Short- and long-
term synaptic depression in rat neostriatum. J. Neurophysiol. 70,
Lynch, G.S., Dunwiddie, T., and Gribkoff, V. (1977). Heterosynaptic
depression: a postsynaptic correlate of long-term potentiation. Na-
ture 266, 737–739.
Maccaferri, G.,andMcBain, C.J. (1995).Passive propagation of LTD
to stratum oriens–alveus inhibitory neurons modulates the tempo-
roammonic input to the hippocampal CA1 region. Neuron 15,
Maccaferri, G., and McBain, C.J. (1996). Long-term potentiation in
distinct subtypes of hippocampal nonpyramidal neurons. J. Neu-
rosci. 16, 5334–1550.
Malinow, R., and Miller, J.P. (1986). Postsynaptic hyperpolarization
during conditioningreversibly blocksinduction oflong-term potenti-
ation. Nature 320, 529–530.
McBain, C.J., and Dingledine, R. (1993). Heterogeneity of synaptic
glutamatereceptors onCA3 st. radiatum interneurones ofrathippo-
campus. J. Physiol. 462, 373–392.
McBain, C.J., DiChiara, T.J., and Kauer, J.A. (1994). Activation of
metabotropic glutamate receptors differentially affects two classes
of hippocampal interneurons and potentiates excitatory synaptic
transmission. J. Neurosci. 14, 4433–4445.
Miles, R., and Wong, R.K.S. (1987). Latent synaptic pathways re-
vealed after tetanic stimulation in the hippocampus. Nature 329,
Mulkey, R.M., and Malenka, R.C. (1992). Mechanisms underlying
induction of homosynaptic long-term depression in area CA1 of the
hippocampus. Neuron 9, 967–975.
Nakajima,S., Franck, J.E., Bilkey, D., andSchwarzkroin, P.A.(1991).
Local circuit synaptic interactionsbetween CA1 pyramidal cellsand
interneurons in the kainate-lesioned hyperexcitable hippocampus.
Hippocampus 1, 67–78.
Ouardouz, M., and Lacaille, J.C. (1995). Mechanisms of selective
long-term potentiation of EPSCs in interneurons of stratum oriens
in rat hippocampal slices. J. Neurophysiol. 73, 810–819.
Sah, P., Hestrin, S., and Nicoll, R.A. (1990). Properties of excitatory
postsynaptic currents recorded in vitro from rat hippocampal in-
terneurons. J. Physiol. 430, 605–616.
Scanziani,M., Malenka,R.C.,andNicoll,R.A. (1996).Roleof intercel-
lular interactions in heterosynaptic long-term depression. Nature
Scharfman,H.E., andSchwartzkroin,P.A. (1990).Responses ofcells
of the rat fascia dentata to prolonged stimulation of the perforant
path: sensitivity ofhilar cellsandchanges ingranule cell excitability.
Neuroscience 35, 491–504.
Schwartzkroin, P.A., and Mathers, L.H. (1978). Physiological and
morphological identification of a nonpyramidal hippocampal cell
type. Brain Res. 157, 1–10.
Schwartzkroin, P.A., and Kunkel, D.D. (1985). Morphology of identi-
fied interneurons in the CA1 regions of guinea pig hippocampus. J.
Comp. Neurol. 232, 205–218.
Sik, A., Penttonen, M., Ylinen, A., andBuzsaki,G. (1995). Hippocam-
pal CA1 interneurons: an in vivo intracellular labeling study. J. Neu-
rosci. 15, 6651–6665.
Sloviter,R.S. (1987). Decreasedhippocampal inhibition anda selec-
tive loss of interneurons in experimental epilepsy. Science 235,
Sloviter, R.S. (1991). Permanently altered hippocampal structure,
excitability, and inhibition after experimental status epilepticus in
the rat: the “dormant basket cell” hypothesis and its possible rele-
vance to temporal lobe epilepsy. Hippocampus 1, 41–66.
Sloviter, R.S. (1992). Possible functional consequences of synaptic
reorganization inthedentategyrusof kainate-treatedrats.Neurosci.
Lett. 137, 91–96.
Sloviter, R.S., and Nilaver, G. (1987). Immunocytochemical localiza-
tion of GABA-, cholecystokinin-, vasoactive intestinal polypeptide-,
andsomatostatin-like immunoreactivityin the area dentata andhip-
pocampus of the rat. J. Comp. Neurol. 256, 42–60.
Stelzer, A., Slater, N.T., and ten Bruggencate, G. (1987). Activation
of NMDA receptors blocks GABAergic inhibition in an in vitro model
of epilepsy. Nature 326, 698–701.
Stelzer,A., Simon, G., Kovacs,G., andRai, R. (1994).Synaptic disin-
hibition during maintenance of long-term potentiation in the CA1
hippocampal subfield. Proc. Natl. Acad. Sci. USA 91, 3058–3062.
Taube, J.S., and Schwartzkroin, P.A. (1987). Intracellular recording
from hippocampal CA1 interneurons before and after development
of long-term potentiation. Brain Res. 419, 32–38.
Taube, J.S., and Schwartzkroin, P.H. (1988). Mechanisms of long-
term potentiation: EPSP/spike dissociation, intradendritic re-
cordings, and glutamate sensitivity. J. Neurosci. 8, 1632–1644.
Tomasulo, R.A., Levy, W.B.,andSteward,O. (1991).LTP-associated
EPSP/spike dissociation in the dentate gyrus: GABAergic and non-
GABAergic components. Brain Res. 561, 27–34.
Synaptic Plasticity in Hippocampal Interneurons
Toth, K., and Freund,T.F. (1992). Calbindin D28k-containing nonpy-
ramidal cells in the rat hippocampus: their immunoreactivity for
GABA and projection to the medial septum. Neuroscience 49,
Wilson, R.C. (1981). Changes in translation of synaptic excitation to
dentate granule cell discharge accompanying long-term potentia-
tion. I. Differencesbetween normal and reinnervated dentate gyrus.
J. Neurophysiol. 46, 324–338.
Wilson,R.C.,Levy, W.B.,andSteward,O.(1981).Changes intransla-
tion of synapticexcitation to dentate granule cell dischargeaccom-
panying long-term potentiation. II. An evaluation of mechanisms
utilizing dentate gyrus dually innervated by surviving ipsilateral and
sprouted crossed temporodentate inputs. J. Neurophysiol. 46,
Wong,R.K.S., andPrince, D.A. (1979). Dendriticmechanismsunder-
lying penicillin-induced epileptiform activity. Science 204, 1228–
Wong,R.K.S., and Traub,R.D. (1983).Synchronized burstdischarge
in disinhibited hippocampal slice. I. Initiation in CA2–CA3 region. J.
Neurophysiol. 49, 442–458.
Zhao, D., and Leung, L.S. (1991). Effects of hippocampal kindling
on paired-pulse response in CA1 in vitro. Brain Res. 564, 220–229.