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The Journal of Neuroscience, February 1, 1999, 19(3):1088-1105
On the Mechanism of the    Frequency Shift in
Neuronal Oscillations Induced in Rat Hippocampal Slices by Tetanic
Stimulation
Roger D.
Traub1,
Miles
A.
Whittington2,
Eberhard H.
Buhl3,
John G. R.
Jefferys1, and
Howard J.
Faulkner2
1 Department of Physiology, University of Birmingham
School of Medicine, Edgbaston, Birmingham B15 2TT, United Kingdom,
2 Department of Physiology, Imperial College of Medicine at
St. Mary's, London W2 1PG, United Kingdom, and 3 Medical
Research Council Anatomical Neuropharmacology Unit, Oxford University,
Oxford OX1 3TH, United Kingdom
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ABSTRACT |
Tetanic stimulation of the CA1 region of rat hippocampal slices can
induce  frequency population oscillations (30-100 Hz) after a
latency of 50-150 msec that are synchronized to within 1-2 msec when
simultaneous stimuli are delivered to two sites 2 mm or more apart.
When tetanic stimuli, twice-threshold for eliciting oscillations,
are used, new phenomena occur. (1) After a period of , there is a
switch to  frequencies (10-25 Hz); (2) during the switch, pyramidal
cell spike afterhyperpolarizations (AHPs) increase and rhythmic EPSPs
occur in pyramidal cells; and (3) after an episode of single-site,
twice-threshold-induced / oscillations, simultaneous two-site
threshold stimuli induce oscillations that are locally
synchronized, but no longer are capable of long-range
synchrony. We studied the cellular mechanisms of the /
switch with electrophysiological techniques and computer simulations.
Our model predicts that the observed increases in both pyramidal cell
AHPs and in pyramidal/pyramidal cell EPSPs are necessary and sufficient
for the switch to occur. Firing patterns generated by the model,
both for pyramidal cells and for interneurons, resemble experimental
records. A one-site twice-threshold stimulus might lead to an inability
of the two sites to synchronize at frequencies, after subsequent
two-site stimulation, via this mechanism. If depression is induced at
synapses coupling pyramidal cells at one site to interneurons at the
other site, then two-site stimulation cannot produce interneuron
doublets; hence, as shown previously, the two sites will be unable to
synchronize. This mechanism works in simulations, and we provide
experimental evidence that synaptic depression and loss of doublets
occur after a sufficiently strong local tetanus to one site. We suggest
that long-range excitatory connections onto interneurons determine
whether different pyramidal cell "assemblies" can synchronize at
frequencies, whereas excitatory connections onto pyramidal cells
determine whether such assemblies can synchronize at frequencies.
Key words:
synaptic plasticity; memory; interneurons; 40 Hz
oscillation; hippocampus; EEG
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INTRODUCTION |
oscillations (>25 Hz) have been
found in vivo in various limbic, olfactory, and neocortical
structures, occurring spontaneously, in response to sensory
stimulation, in association with motor performance, or after electrical
stimulation of certain brainstem and diencephalic nuclei [for review,
see Gray (1994) and Singer and Gray (1995); see also Ribary et al.
(1991), Murthy and Fetz (1992), Barth and MacDonald (1996), Steriade
and Amzica (1996)]. It is possible that oscillations play an
important role in information processing, either by providing a means
for "coincidence detection" (König et al., 1996) or by other
cellular mechanisms. oscillations (10-25 Hz) have also been
recognized in cortical structures (Leung, 1992), for example, during a
sensorimotor task (Roelfsema et al., 1997), but also in humans taking
sedative drugs (Glaze, 1990). A shift from to frequencies has
been observed in human neocortical event-related potentials (Pantev,
1995, his Fig. 5). The functional significance of frequency
oscillations is unknown, and the mechanisms of different sorts of oscillations may not be identical.
The evidence supporting a functional role for oscillations is
intriguing, yet also circumstantial. Better understanding of the
cellular mechanisms of both and oscillations may prove important, insofar as it could lead to means of manipulating the phenomenon in transgenic animals and observing the consequences. An
analogous program has been initiated with NMDA receptor-mediated long-term potentiation (LTP) (McHugh et al., 1996).
As in the study of epileptogenesis, brain slices have proven to be
useful in elucidating the cellular mechanisms of -frequency neuronal
oscillations, although it remains to be proven that the mechanisms
operative in vitro are the same as those operative in
vivo. Briefly, we know that what happens in the CA1 region of rat
hippocampal slices is as follows.
(1) Pharmacologically isolated networks of interneurons, presumably
including basket cells, oscillate synchronously during tonic activation
of interneuronal metabotropic receptors, the frequency and synchrony
being regulated by interneuron  interneuron GABAA
receptor-mediated synaptic connections (Whittington et al., 1995; Traub
et al., 1996a). This type of synchrony does not extend over long
distances, and 1.2 mm is an upper bound on the distance over which
"interneuron network " synchrony can extend in the rat CA1
region in vitro (Whittington et al., 1997a).
(2) Tetanic stimulation can elicit, after a delay of tens of
milliseconds or more, a oscillation extending ~400 µm from the
stimulus (Colling et al., 1998). This "pyramidal/interneuron network
" (PING) is associated with population spikes; in addition, interneurons and pyramidal cells fire in phase, to within a few milliseconds. During PING, both cell types experience a long (hundreds of milliseconds or more) and large depolarization, mediated at least
in pyramidal cellsmainly by metabotropic glutamate receptors (Whittington et al., 1997a). The oscillation is not time-locked to
the stimulation.
(3) PING is capable of synchronizing to within 1 or 2 msec,
over distances up to 4.5 mm, when two sites are tetanically stimulated together. This occurs despite an estimated pyramidal cell axon conduction velocity of 0.5 m/sec (hence conduction time for 4.5 mm = 9 msec), and despite the fact that basket cell axons extend only
~500 µm in either direction from the cell body (Buhl et al., 1994a). After two-site stimulation, but not after one-site stimulation, interneurons often fire in spike doublets, with intradoublet intervals of ~5 msec.
(4) Long-range synchrony of PING actually requires the
occurrence of doublets in network simulations, the latter indicating that the second spike of the doublet, but not the first, is
inducedvia AMPA receptorsby the synchronized pyramidal cell spike
(Traub et al., 1996b; Whittington et al., 1998). AMPA receptor blockade eliminates long-range synchrony of PING, consistent with this prediction (Whittington et al., 1997a). The mechanisms by which interneuron doublets favor long-range synchrony have been analyzed theoretically by Ermentrout and Kopell (1998). The fact that two-site stimulation is necessary for interneuron doublets to occur suggests that long-range pyramidal cell interneuron connections contribute critically to the generation of the interneuron doublets.
(5) When PING is evoked by an especially strong tetanic stimulus
(twice-threshold intensity, designated 2×T, compared with threshold
stimuli, designated 1×T), the oscillation is followed by a
relatively abrupt transition to a period of synchronized oscillation (10-25 Hz); here, "threshold" means "threshold for evoking the oscillation." This occurs with either one-site or two-site stimulation, and in the latter case the is synchronized between the two sites. During , a rhythm continues in the
interneurons, detectable as a ripple in the field potential and as
-frequency IPSPs in pyramidal cells (Whittington et al., 1997b).
(6) During the transition in vitro, two events
are notable in pyramidal cells: a return toward normal of fast-spike afterhyperpolarizations (AHPs) (which are largely blocked during itself, presumably because of the action of metabotropic glutamate receptors), and the development of -frequency, AMPA
receptor-dependent EPSPs, which can reach >5 mV in amplitude. During
itself, pyramidal cells sometimes fire spike doublets, and
population spike doublets also can occur, a phenomenon that is rare
during oscillations in the CA1 region (Whittington et al., 1997b);
population spike doublets can occur, however, during oscillations
in the subiculum (Stanford et al., 1998).
(7) A single administration of 2×T stimulation produces long-lasting
changes at synaptic and network levels. For a period of hours, a
subsequent 1×T stimulation leads to rhythmic EPSPs in pyramidal cells,
as well as to a oscillation after the initial oscillation. If
the 2×T stimulation is given to both sites simultaneously, subsequent
1×T stimulation (simultaneously to both sites) leads to followed
by at the two sites, with both oscillations synchronized between
the two sites. Most remarkably, if a single administration of 2×T
stimulation is given to one site only, subsequent 1×T
stimulation at the two sites leads to oscillations that no longer
are capable of synchronizing together (Whittington et al., 1997b).
The aims of the present study are these: (1) to develop a detailed
network model that replicates the known physiology of in vitro oscillations, including interneuron doublets (the model should contain about as many neurons as in the experimental preparation and also contain different physiological/anatomical types of
interneurons); (2) to demonstrate the predictive power of this model,
by comparing the effects of blocking pyramidal cell interneuron
connections at one site, in model and experiment [the latter performed
with joro spider toxin, a blocker of certain interneuron AMPA receptors (Iino et al., 1996)]; (3) to show in the model that the development of
EPSPs and simultaneous increases in pyramidal cell spike AHPs are
sufficient to account for the abrupt frequency transition (this idea was tested experimentally by blocking EPSPs, using pressure
ejection of NBQX); and (4) to offer a hypothesis about why one-site
2×T stimulation prevents future synchronization of oscillations
and to present experimental evidence that supports this hypothesis.
Our data will suggest a more general hypothesis concerning a role for
oscillating neuronal assemblies in memory.
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MATERIALS AND METHODS |
Experimental methods
Transverse dorsal CA1 hippocampal slices 400-450 µm thick
were prepared from brains of 24 Sprague Dawley rats (200-250 gm) that
were killed by cervical dislocation followed by decapitation. Slices
were maintained at 34-35° at the interface between warm, wetted 95%
O2-5% CO2 and artificial CSF (ACSF) containing
(in mM): NaCl 135, KCl 3, NaHCO3 16, NaH2PO4 1.25, CaCl2 1.5-2,
MgCl2 0.8, D-glucose 10.
To evoke oscillations, tetanic stimuli were delivered to stratum oriens
at either of two sites (CA1a and CA1c; separation, 1.5-3 mm) or to
both sites together. Each stimulus consisted of 20 pulses, 50 µsec
duration, at 100 Hz. In each slice, the stimulus voltage was adjusted
to be either threshold for evoking an oscillation (1×T; value, 4-12
V) or twice-threshold (2×T). Four different combinations of sites and
stimuli were used: (1) 1×T to one site; (2) 1×T to both sites; (3)
2×T to one site; and (4) 2×T to both sites. In the same slice, at
different times, one or another combination could be used, but we did
not apply 1×T stimulation at one site simultaneously with 2×T
stimulation at the other site. Extracellular field potentials were
recorded at the two sites in stratum pyramidale with glass
microelectrodes filled with 2 M NaCl (1-5 M ).
Intracellular recordings were taken from presumed pyramidal cells and
interneurons in stratum pyramidale, distinguished by physiological
criteria as described in Whittington et al. (1997a). Glass
micropipettes were filled with 2 M potassium acetate or methylsulfate (30-65 M). Recordings were digitized and analyzed using a CED analog/digital converter and associated software, including
Spike2 (Cambridge, Electronic Design, Cambridge, UK).
In some experiments, drugs were puffed (pressure ejected) onto the
tissue, using a glass micropipette with the tip broken (100-500 k)
and a pressure of 60 psi for 50-150 msec. Drugs were dissolved in
ACSF, including 20 µM NBQX (Tocris) and 0.1 µM joro spider toxin (RBI, Natick, MA; Sigma, St. Louis,
MO). NBQX was puffed onto stratum oriens at a position
approximately midway between the two stimulation sites. Joro toxin was
puffed onto stratum pyramidale near one stimulation site.
Simulation methods
General comments on modeling large neuronal
populations. The experimental observations in this study are not
readily distilled into a single number, such as a relaxation time
constant or a reversal potential. Rather, they consist of firing
patterns generated by a large population of neurons. How, then, can one
compare simulation results with experiments? This is a familiar issue
in the physics of many interacting elements (phase transitions,
turbulence). We are likewise seeking to replicate and understand the
behavior of a complex system. Our approach involves three elements.
(1) Model neurons should fire singlets, doublets, or bursts in
situations in which corresponding real neurons do. The frequency of
firing of pyramidal neurons and of interneurons should agree with the
experiment. These features are what we shall mean by "firing
patterns." In the future, when there is a deeper understanding of the
oscillations, more subtle characteristics of the data may become
amenable to analysis.
(2) When simulation traces differ from experimental ones in some
detail, as in the shape of an afterpotential, the reason should be
explicable, and one should be able to show that this difference is not
critical when it comes to determining firing patterns. We cannot claim
to reproduce every single aspect of the experimental recordings, so
that simulation and experimental data are indistinguishable. To show
that some features of the simulation data are not critical for
determining firing patterns, it is helpful to construct a "reduced"
model (although this remains to be accomplished for oscillations).
For example, the existence of interneuron doublets and their importance
for long-range synchrony was predicted with a model using
multicompartment neurons and a deterministic (and not very realistic)
connection topology (Traub et al., 1996b). After experiments
showed that interneuron doublets actually existed and were important in
two-site synchronization (Traub et al., 1996b; Whittington et al.,
1997a), Ermentrout and Kopell (1998) captured the essential
physics of doublets in a model with only four single-compartment
neurons. In this way, Ermentrout and Kopell (1998) highlighted
the essential features of the system (the axon conduction delay between
the sites, the precision and strength of synaptic excitation of
interneurons), and one could learn also which features are
not essential (e.g., the exact shape of the synaptic
potentials), at least those that are not critical for this problem. In
a similar way, simplified models exist for related phenomena, including
interneuron network (Wang and Buzsáki, 1996; White et al.,
1998); analysis of such models provides clues about which parameters in
the system are most critical for shaping the oscillation.
(3) The model must be predictive. The predictions can take several
forms. (1) If the model is adjusted in some way to replicate the firing
patterns of one sort of cell (e.g., pyramidal cells), then the firing
patterns of the other sort of cells (e.g., interneurons) should be
appropriate (see Figs. 4, 5). (2) A change in an identified parameter
(e.g., the AMPA receptor-mediated conductance on a population of
interneurons) should lead to a defined change (or lack of change) in
firing patterns (see Fig. 3). (3) Conversely, a known change in firing
pattern may imply a change in some particular parameter (see Figs. 10,
11). All of these types of prediction are experimentally testable.
This general approach has been used to study not only oscillations
in vitro, including the effects of anesthetic agents (Whittington et al., 1998), but also in vitro
epileptogenesis (Traub et al., 1993, 1995).
Overall model structure. The model contained 3072 pyramidal
cells (arranged in a 96 × 32 array), and 384 inhibitory cells, arranged in four rows, each containing 96 interneurons. The first of
these rows consisted of "basket cells," the second of "axo-axonic cells," the third of "bistratified cells" (Halasy et al., 1996), and the fourth of "oriens/lacunosum-moleculare (o/lm) cells" (Sik et al., 1995). The row-dimension (96 cells) is taken to represent a
length along CA1 stratum pyramidale of 1.92 mm. Pyramidal cell axons
are allowed to contact cells anywhere in the array, but interneurons
can contact only cells within some specified distance of the cell body
(Fig. 1; see also below).
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Figure 1.
Structure of CA1 network model. The model consists
of two interconnected arrays. The pyramidal cells (e-cells,
top) are arranged in a 96 × 32 array, representing
1.92 mm along the long axis. Pyramidal cells contact other cells
(pyramidal cells and interneurons) with probability that is independent
of distance. The four types of interneurons (i-cells,
bottom)axo-axonic cells, basket cells, bistratified
cells, and o/lm cellsare laid out in four lines of 96 interneurons
each, one line for each type of interneuron. Interneurons contact other
cells (either pyramidal cells or interneurons, except that axo-axonic
cells do not contact interneurons), with probability that is uniformly
random but subject to a constraint: presynaptic and postsynaptic cells
must lie within 500 µm of each other along the long axis.
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Intrinsic cell properties. For pyramidal cells, we began
with a multicompartment CA3 pyramidal cell model (Traub et al., 1994). This model is a refinement of an earlier model based, in part, on
voltage-clamp data (Traub et al., 1991). The soma-dendritic membrane
contains the following active conductances: fast
gNa, a single type of high-threshold
noninactivating gCa, a "delayed rectifier" gK, a transient "A" type
of gK, a slow
Ca2+-dependent
gK(AHP), and the faster voltage- and
Ca2+-dependent gK(C). Other
conductances were not simulated: persistent gNa
and several types of gCa and
gK, including the M conductance. This
single-cell model can generate intrinsic bursts in response to current
pulses or sustained dendritic currents and the transition from
low-frequency bursting to higher frequency single spikes as the soma is
depolarized. It does not always accurately reproduce spike
afterpotentials, probably because of the incomplete repertoire of
conductances. gCa density was multiplied by 0.5 to reduce the tendency to intrinsic bursting. In addition,
gK(AHP) density was reduced to 25% of its usual
value during the oscillation [simulating one effect of
metabotropic glutamate receptors, which are known to be activated
during tetanically induced activity (Whittington et al., 1997a)],
but this density returned to its usual value during the oscillation. This is in accordance with experimental observations on
the recovery of fast-spike AHPs during the / transition
(Whittington et al., 1997b), together with our presumption that slower
AHPs recover as well. Recovery of fast-spike AHPs may result from a
wearing off of the metabotropic glutamate receptor-mediated suppression
of IM (Charpak et al., 1990), or some other
relatively fast K current, but metabotropic glutamate receptors also
suppress IK(AHP) (Charpak and Gähwiler,
1991), and this conductance would be expected to recover as well. (Note
that we cannot simulate time-dependent changes in
gK(M) because this conductance is not included
in the single-cell model, but fast AHPs should not significantly influence the oscillation, whose frequency is 10-25 Hz (period 40-100 msec). Slow AHPs, on the other hand, could well influence the
oscillation by causing pyramidal cells to "skip beats" of the
underlying activity that persists during ; see below).
For interneurons, we began with the multicompartment model of Traub and
Miles (1995), but we multiplied dendritic gNa
and gK densities by 0.1 to allow for the low
probability in CA1 of a single pyramidal cell spike causing an
interneuron spike. In our simulations, the different sorts of
interneurons had identical intrinsic properties, although their
connectivity patterns and postsynaptic actions were different. We
judged that insufficient data exist to justify distinguishable models
of the various interneuron intrinsic properties and that the additional
complexity was not justified for this stage of the model.
Both pyramidal cells and interneurons were excited with a constant or
slowly varying excitatory synaptic conductance, intended to represent
cellular excitation mediated by metabotropic receptors (Guérineau
et al., 1995; Whittington et al., 1997a). In the model, this
conductance had a reversal potential of 60 mV positive to resting
potential. For pyramidal cells, the total conductance was 55-60 nS in
some cases and 60-62 nS in other cases. The conductance was chosen to
be large enough so that the cells would fire on all or almost all waves, as observed experimentally (Whittington et al., 1997a). The
conductance was spread over the distal basilar dendrites and the apical
dendrites [levels 1 and 5-11 in Traub et al. (1994)]. For
interneurons, the total "driving" conductance was 10.0-10.2 nS,
distributed over levels 3-5 and 9-11 (Traub and Miles, 1995, their
Fig. 1). Again, this conductance was chosen to be large enough so that
the interneurons would fire on each wave.
Synaptic connectivity. Pyramidal cells could contact other
neurons (either other pyramidal cells or interneurons) with a
probability that was independent of location of either presynaptic or
postsynaptic cell. This rule did not take into account the known
anatomical asymmetry of CA1 pyramidal cell connections, when axons
running toward the subiculum are compared with axons running toward CA2 (Tamamaki and Nojyo, 1990). (The anatomical asymmetry has so far not
been shown to have physiological consequences for two-site tetanically
evoked oscillations, in that systematic differences have not been noted
between stimulating one end of CA1 vis-á-vis the other.) In
contrast to pyramidal cells, interneurons could only contact other
cells (either pyramidal cells or interneurons) that were within 25 cell
diameters (500 µm) of the presynaptic neuron, measuring along the
long axis of the model array and ignoring the short axis. Within this
"allowed region" for contacts, all connections had equal
probability. The connectivity patterns of the different sorts of
interneurons were identical, in a statistical sense. The latter two
details of interneuron connectivity do not accord precisely with known
anatomy, but our scheme does capture the relative spatial localization
of interneuron synaptic outputs vis-á-vis pyramidal cell outputs.
Each pyramidal cell received synaptic input from 30 other pyramidal
cells. Connections from one pyramidal cell to another were made to a
single compartment in the basilar dendrites of the postsynaptic cell
(Deuchars and Thomson, 1996); in reference to Traub et al. (1994),
allowed contact sites were in levels 2 and 3. The mean connection
probability, 30/3072 = 0.98%, is similar to the connection
probability (9/989 = 0.91%) estimated by Deuchars and Thomson
(1996).
Each interneuron received synaptic input from 150 pyramidal cells. The
contact sites were single compartments (Buhl et al., 1994a) in levels
1, 2, and 6-8 (Traub and Miles, 1995).
Each pyramidal cell received synaptic input from a total of 80 interneurons, 20 of each type [i.e., basket (Buhl et al., 1994a), axo-axonic (Buhl et al., 1994b), bistratified, o/lm]. Basket cells contacted the perisomatic region (levels 3-5), axo-axonic cells contacted the axon initial segment, bistratified cells contacted the
middle and distal basilar dendrites (levels 1 and 2) and the middle
apical dendrites (levels 6-9), and o/lm cells contacted the distal
apical dendrites (levels 10-11). Except for axo-axonic cells, the
synaptic contacts were spread over all of the compartments in the
respective levels.
Each interneuron received synaptic input from a total of 60 interneurons, 20 of each type, except for axo-axonic cells, which do
not appear to contact other interneurons (Buhl et al., 1994b). Interneuron contacts took place on single compartments in the proximal
dendrites, levels 3 and 5.
Synaptic actions. Only AMPA and GABAA
receptor-mediated actions were simulated for connections between
neurons. AMPA receptor-mediated conductances had a reversal potential
60 mV positive to resting potential, and GABAA
receptor-mediated conductances had a reversal potential  15 mV
relative to resting potential. The time course of the unitary synaptic
conductances (in nS) were as follows: (1) pyramidal cell pyramidal
cell: g × t × e( t/2), g ranging from 0.0 to 3.45 (and t in msec); (2) pyramidal cell interneuron:
2 × t × et (this
scaling constant of 2 allows the interneuron to develop doublets when
enough presynaptic neurons are firing synchronously); (3) axo-axonic
cell or basket cell pyramidal cell: jump to 1.5 nS over 1 time
step, then exponential decay with time constant 10 msec (Traub et al.,
1996a); (4) bistratified cell or o/lm cell pyramidal cell: jump to
1.5 nS over 1 time step, then exponential decay with time constant 50 msec (Pearce, 1993); (5) basket cell interneuron: jump to 2.0 nS
over 1 time step, then exponential decay with time constant 10 msec;
and (6) bistratified cell or o/lm cell interneuron: jump to 0.2 nS
over 1 time step, then exponential decay with time constant 50 msec.
When several presynaptic cells fire, and these presynaptic cells
contact the same compartment of the postsynaptic cell, then the
resulting conductances are simply added together. There are saturation
effects (in place for the sake of numerical stability): GABAA conductances cannot exceed 8 nS/compartment on
interneurons; AMPA conductances cannot exceed 8 nS/compartment on
pyramidal cells or 5 nS/compartment on interneurons. We did not
simulate time-dependent synaptic depression or facilitation.
Axon conduction velocity was 0.5 m/sec for pyramidal cell axons
(Colling et al., 1998) and 0.2 m/sec for interneuron axons (Salin and
Prince, 1996).
Noise in the system was simulated by having random ectopic spikes,
originating in axons, with Poisson statistics and independently in
different cells: averaging 1 ectopic spike per 10 sec in pyramidal cells and 1 per 5 sec in interneurons. These ectopic spikes propagate both antidromically and orthodromically to cause spontaneous synaptic potentials.
The program saved the somatic potential of selected pyramidal cells
and interneurons and local average potentials (of 224 pyramidal
cells or of 28 interneurons) at two sites, one at either end of the
array (locations 5 and 91 along the long axis of the array).
Simulations were run for 1.5-2 sec of "neuronal" time.
Time-dependent parameter changes, such as for EPSC amplitude or
gK(AHP) amplitude, took place over an interval
in the middle of this time period. Neuronal activity is illustrated
either for steady-state activity at the end of a run or for a time
period spanning the interval of parameter changes, i.e., the interval
over which the / transition takes place. Autocorrelations and
cross-correlations were computed for intervals of at least 200 msec for
activity and 800 msec for activity.
The code was written in FORTRAN with extra instructions for a parallel
supercomputer, an IBM SP2 with 12 nodes. The approach to adapting a
network algorithm to a parallel machine is described in Traub et al.
(1995). The pseudo-random number generator used was part of an IBM
software package, ESSL. The differential equations were integrated
using a second-order Taylor series method [described in Traub and
Miles (1991)], with a fixed integration step, 2.5 µsec for pyramidal
cells (Traub et al., 1994) and 1.25 µsec for interneurons (Traub and
Miles, 1995). In the original studies of single cells, a range of
integration steps was tried, and the values used here were shown to
yield stable results. Simulations took ~1 hr to run per 100 msec.
(For details about the code, contact r.d.traub{at}bham.ac.uk.)
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RESULTS |
Validation of network model
Simulation of oscillations evoked by one- and
two-site stimulation
Before using the network model to study oscillations, it was
necessary to show that it could replicate the basic physiology of oscillations. First, it was shown by tonically exciting the interneurons alone and by disconnecting the pyramidal cells that the
interneuron subnetwork would generate -frequency oscillations that
were locally synchronized but could not synchronize to within 1 msec
across the 1.92 mm extent of the array (data not shown). This result is
in agreement with previous experimental and simulation results
(Whittington et al., 1997a). In part, this result implies that with the
parameter choices used, the isolated interneuron subnetwork's behavior
is dominated by IPSCs whose  GABA(A) is 10 msec, rather
than the longer-duration IPSCs induced by the dendrite-contacting interneurons.
We next stimulated pyramidal cells and interneurons simultaneously,
with tonic excitatory conductances, either in one-half of the array (to
simulate one-site stimulation) or in the whole array (to simulate
two-site stimulation) (Fig. 2). The
following experimental features (Traub et al., 1996a,b;
Whittington et al., 1997a) of tetanically evoked oscillations were
thereby replicated. (1) Both pyramidal cells and interneurons fired at
frequencies, gated by GABAA IPSPs; (2) interneurons
fired in doublets after two-site stimulation but not after one-site
stimulation; (3) there was synchrony both locally and across the array
(phase lag 1 msec for two-site stimulation), the latter a consequence
of interneuron doublet firing; (4) pyramidal cells fired approximately
in phase with interneuron singlets during one-site stimulation (mean
lag from pyramidal cell to interneuron, 1.3 msec), and with the first spike of the interneuron doublet during two-site stimulation (mean lag
from pyramidal cell to interneuron 2.8 msec); and (5) the oscillation
frequency was faster during one-site stimulation (62 Hz) than during
two-site stimulation (41 Hz), again, a consequence of interneuron
doublet firing during the latter case.
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Figure 2.
Network model generates locally synchronized oscillation with interneuron singlets and globally synchronized
oscillation with interneuron doublets. The network was simulated
according to two paradigms. To represent two-site stimulation, driving
conductances were applied to all of the neurons (60 + x
nS total for e-cells, x ranging from 0 to 2.0 nS; and 10 + x nS for i-cells, x ranging from 0 to
0.2 nS). To represent one-site stimulation, the same conductances were
applied, but to cells in the left half of the array only. Pyramidal
cells did not excite each other, and maximal
gK(AHP) was 0.25 × its standard value.
A, Intracellular potentials. With two-site
stimulation (left), pyramidal cells on the
right (e-cell 2) and left (e-cell 1) of
the array oscillate synchronously. Interneurons fire doublets, or
singlets followed by an EPSP, and the first spike in the doublet is
approximately in phase with nearby pyramidal cells. With
one-site stimulation (right),
interneurons fire singlets only. B, Autocorrelations and
cross-correlations of local averages of e-cell voltages (224 cells).
With two-site stimulation, the two-site cross-correlation peak is at 1 msec. Note that oscillation frequency is higher with one-site
stimulation (right, 62 Hz) than with two-site
stimulation (left, 41 Hz). These results are in
agreement with experimental data on in vitro oscillations (Traub et al., 1996a,b; Whittington et al., 1997a).
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These features have been replicated in the previously used "chain"
model of five cell groups in a row (Traub et al., 1996a,b; Whittington
et al., 1997a), with the exception of (2), the specificity of
interneuron doublet-firing for two-site (but not one-site) stimulation. The reason for this improved specificity of the
present model is simple: there are long-range excitatory
connections in the present model but not in the chain model.
Instead, an interneuron in the chain model receives excitatory
inputs from pyramidal cells in its own group and from pyramidal cells
in immediately neighboring group(s). In the chain model, during a
synchronized oscillation, the total excitatory input received by the
interneuron will be the same, whether three groups or five groups are
oscillating. However the unitary AMPA conductance is chosen, the
interneuron either fires doublets (for a large conductance), or it does
not (for a small conductance). On the other hand, when there are
long-range excitatory connections, as well as local ones, then there is
a range of unitary AMPA conductances such that (1) a local oscillation cannot induce doublets, but (2) a more global oscillation can.
We note that doublet firing by interneurons during CA1 two-site
synchronized oscillations is reminiscent of -frequency bursts in
neocortical neurons, morphologically identified as aspiny (hence
presumably inhibitory) cells (Steriade et al., 1998).
The simulations in Figure 2 were performed without recurrent excitation
between pyramidal cells; such interactions do not appear to be
necessary for oscillations in CA1. Nevertheless, as Figure 4 will
show, synchronized oscillations can also exist in our model when
there is recurrent pyramidal/pyramidal cell excitation, provided it is
not too powerful.
We will present evidence that the long-range excitatory connections
onto interneurons are important for understanding the two-site desynchronization that follows twice-threshold stimulation of a single site.
Effects of joro spider toxin
Joro toxin relatively selectively blocks AMPA receptors lacking
the GluR-B (GluR2) subunit. Such AMPA receptors are
Ca2+ permeable and are more prevalent on
interneurons than on pyramidal cells (Geiger et al., 1995; Iino et al.,
1996), so that the toxin is relatively specific for interneurons.
Experimental application of joro toxin during a tetanically evoked
oscillation and simulation of its effects allow a further test of the
model. Based on our understanding of the oscillation mechanisms,
blockade of interneuron AMPA receptors in one region should lead to
loss of interneuron doublets in that region. This loss would lead to
two effects: the doublets would no longer be available to provide
timing information to maintain synchrony (Ermentrout and Kopell, 1998),
and the network oscillation frequency of the poisoned region would be
faster than that of the unpoisoned region (if the latter is able to
generate doublets), which would in turn lead to complex interference
effects between the two regions.
Figure 3A illustrates a
simulation of the effects of joro toxin, obtained by blocking
interneuron AMPA receptors in the left half of the array, whereas
gK(AHP) was at its "standard" value. (This
value was used because the corresponding experimental recordings were
obtained during the phase of the oscillation. Please note also the
different time scales for pyramidal cells and interneurons.) As
expected, interneurons in the left half fire only in singlets (Fig.
3Aii). In addition, interneurons in the right half of the array (data not shown), although able to fire doublets, do not fire
nearly as many doublets as in comparable control simulations. This
reduction in doublet incidence is related to the loss of two-site
synchrony in this simulation (mean phase lag between the two sites, 5 msec). It will be recalled that excitatory input from both nearby and
distant cells is required for interneuron doublet generation (Fig. 2)
and that doublets are both a consequence of and a contributor to
long-range synchrony. Pyramidal cells in this simulation demonstrate
irregular firing patterns, which are not a consequence of any obvious
irregularity in the firing patterns of the interneurons. The
irregularity may result from recurrent EPSPs impinging on pyramidal
cells from the two array regions, because they "try" to oscillate
at different frequencies. Note that pyramidal cells fire on selected
peaks of the intracellular waves, which are generated by the
interneuron network.
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Figure 3.
Effects of locally applied joro toxin on
oscillations evoked by two-site stimulation: model and experiment.
A, Simulation. The effect of locally applied joro toxin
was simulated by blocking AMPA receptors on interneurons in the
left half of the array. Near-uniform tonic excitatory
conductances were applied to pyramidal cells and interneurons, as in
Figure 2 (left). gK(AHP)
density was set at its standard value, and unitary pyramidal/pyramidal
EPSCs were 0.75 × t × et/2 nS. Model interneurons in the
left half of the array do not fire doublets [with their
AMPA receptors blocked (cf. Whittington et al., 1997a, 1998)], whereas
interneurons in the right half of the array do fire
doublets. As a result, the two halves of the array tend to oscillate at
different frequencies (Fig. 2), but the array halves are synaptically
coupled by interneurons around their boundaries and by pyramidal cells
globally. This in turn causes complex irregular firing patterns in the
pyramidal cells. B, Experiment. Two-site oscillations
were evoked by simultaneous tetanic stimulation in the CA1 region. Joro
toxin (0.1 µM), a blocker of interneuron AMPA receptors,
was pressure-ejected onto the tissue near site 1 in stratum pyramidale.
Cells were recorded near the site of toxin injection. The toxin
produces irregularity in the firing patterns of pyramidal cells and
abolishes interneuron doublets. Note the different time scales for
pyramidal cells and interneurons.
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Figure 3B illustrates data from experiments (four slices) in
which joro toxin (0.1 µM) was pressure-ejected near one
stimulation site in CA1 stratum pyramidale, immediately after a
two-site twice-threshold tetanic stimulation. Subsequent tetanically
evoked oscillations (evoked at 4 min intervals) exhibited firing
patterns as shown. Pyramidal cells during the phase of the
oscillation fire on some of the peaks of intracellular waves (Fig.
3Bi, control), but after joro toxin application,
pyramidal cells also can fire in rapid runs (Fig. 3Bi, bottom
trace), as in the simulation. In control conditions, interneurons
could fire spike doublets (Fig. 3Bii), but such doublets
were not observed after joro toxin (Fig. 3Bii, bottom
trace), consistent with simulations and consistent with the
expectation that the second spike in the interneuron doublet is evoked
by AMPA receptor activation, the latter being reduced by joro toxin.
The mean phase lag for four oscillation epochs after joro toxin was
2.3 msec, versus 1.8 msec for control oscillations (not statistically
significant), i.e., there was less of an effect on phase than in the simulation.
Mechanism of frequency shift
Simultaneous increases in the amplitude of unitary EPSCs and of
AHPs can account for the frequency shift
Whittington et al. (1997b) showed that during the transition from
to frequencies, two parameters in the neuronal system changed,
with comparable time courses (over approximately 10 oscillation cycles
or several hundred milliseconds): (1) pyramidal cell spike AHPs
increased from a value of <1 mV to a value of >4 mV, and (2) AMPA
receptor-mediated EPSPs in pyramidal cells, in phase with the
oscillation, increased from a value of  0.25 mV to a value of >2 mV.
These EPSPs are not an epiphenomenon of increased firing synchrony of
the pyramidal cells, because the magnitude of population spikes does
not increase, and may even decrease, over the time interval in
question; thus, the increase in EPSP size is presumed to reflect a true
increase in the magnitude of unitary EPSCs at recurrent CA1 pyramidal
cell/pyramidal cell connections.
During the period when spike AHPs and EPSPs are increasing, pyramidal
cells remain depolarized (Whittington et al., 1997b). In view of the
apparent increase in K+ current(s) over this period,
it is unlikely, therefore, that the metabotropic glutamate
receptor-mediated conductance, induced by the tetanic stimulation
(Whittington et al., 1997a), diminishes much during the oscillation.
Figure 4 illustrates a simulation in
which tonic excitatory conductances to pyramidal cells and to
interneurons were kept constant. For the first 800 msec of the
simulation, maximum gK(AHP) was held constant at
0.25× its usual value, and unitary pyramidal/pyramidal EPSCs were
0.75 × t × et/2
nS. During this time, the array generated a frequency oscillation, synchronized across the array to within 1 msec; pyramidal cells fired
singlets and interneurons fired either doublets or singlets followed by
EPSPs. Subsequently, during the interval shown by the ramp (800-1200
msec from simulation onset), linearly in time, maximum
gK(AHP) was increased fourfold (to its standard
value) and unitary EPSC amplitude was increased 4.6-fold. Both local and long-range EPSCs were increased in tandem. In the course of the
800-1200 msec interval, and after it, oscillation frequency slows from
52 to ~14 Hz; the large EPSPs in a hyperpolarized pyramidal cell
during the phase indicate that the oscillation is synchronized, as do local average potentials (data not shown). In the phase, pyramidal cells fire occasional doublets [as occurs experimentally (Whittington et al., 1997b)], and interneurons fire in bursts, as well
as singlets and doublets. Autocorrelations and cross-correlations of
average pyramidal cell signals are shown in Figure
4B. Note that during the phase (Fig.
4Bii), there is a smaller peak at 30 Hz, slower
than the frequency during the initial oscillation (Fig.
4Bi); this slowing is a consequence, in part, of
interneuron bursts.
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Figure 4.
Firing patterns of pyramidal cells and
interneurons during and oscillation: simulation. The /
switch was simulated by applying tonic excitatory conductances to
pyramidal cells and interneurons, with maximal
gK(AHP) at 0.25 × its standard value
and unitary pyramidal/pyramidal EPSCs 0.75 × t × et/2.
Starting at 800 msec after onset of the run, and until 1200 msec (shown
by the ramp), maximal gK(AHP) and unitary
EPSCs increased, linearly in time to new values that then remained
constant. The new values were maximal
gK(AHP) = standard value, unitary
pyramidal/pyramidal EPSC 3.45 × t × et/2. A, Two pyramidal
cells (at x = 5 and x = 91, the
latter hyperpolarized with 3 nA current to reveal EPSPs), and a basket
cell. During the oscillation, pyramidal cells fire singlets, and
interneurons fire doublets or singlets followed by EPSPs. As
gK(AHP) and unitary EPSCs increase, the
pyramidal rhythm slows to frequency, pyramidal cells sometimes fire
doublets, and interneurons fire singlets, doublets, and bursts. During
the phase, pyramidal cells exhibit subthreshold synaptic potentials
at frequency [see also Whittington et al. (1997b)].
B, Autocorrelations and cross-correlations of e-cell
average signals, during the phase (i, 52 Hz, phase
lag between sites 1.7 msec), and during the phase
(ii, 14.3 Hz). During the phase, there is a small
peak in the autocorrelation at frequency (30 Hz).
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The -phase EPSPs in Figure 4 reach ~10 mV, whereas experimental
-phase EPSPs are <5 mV. It is possible that model neurons, in which
EPSPs are pictured, are more hyperpolarized than corresponding real
neurons, an effect that would increase EPSP size.
We repeated the simulation of Figure 4, but with tonic driving
conductances delivered to pyramidal cells and interneurons in the left
half of the array only, with maximum gK(AHP) and
unitary EPSCs evolving as in Figure 4. This simulation (data not shown) verified that the model could replicate the shift induced by strong stimulation at a single site (Whittington et al., 1997b).
In summary, in simulations, an increase in
gK(AHP) with a simultaneous increase in unitary
pyramidal/pyramidal EPSCs (that is, sufficiently large) produces a
"switch" from synchronized to a synchronized oscillation.
The latter contains "underlying" that is generated by the
interneuron network, pyramidal cell doublets (on occasion), and
interneuron bursts.
Clear frequency shifts have been recorded intracellularly
in >50 pyramidal cells and in two interneurons in the course of this
study. Examples are shown in Figure
5A. This particular pyramidal
cell did not exhibit spike doublets during ; an example of pyramidal
cell spike doublets is shown in Whittington et al. (1997b, their Fig.
1Cc). Subthreshold membrane fluctuations are clearly seen during the
phase of the pyramidal cell in Figure 5A (compare Fig.
4A). The interneuron (not recorded simultaneously with the pyramidal cell) fires in a complex mixture of single spikes,
doublets, triplets, and quadruplets during the phase, as occurs
also in the simulation (Fig. 4).
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Figure 5.
Firing patterns of pyramidal cells and
interneurons during and oscillation: experiment. Oscillations
were evoked by two-site twice-threshold stimulation, with traces
showing the stimulus artifacts. Note that, as shown previously
(Whittington et al., 1997a), the oscillations are superimposed on slow
membrane depolarizations. Dotted lines show resting
membrane potentials. A, Intracellular transitions in a pyramidal cell and an interneuron (not simultaneous).
The switch occurs approximately 200 msec into the
recording. This particular pyramidal cell does not fire doublets during
but does exhibit subthreshold membrane fluctuations. The
interneuron fires a doublet during ; during it fires singlets,
doublets, a triplet, and a quadruplet. B, Laminar field
potentials were obtained in simultaneous pairs (the stratum oriens and
stratum pyramidale recordings were simultaneous in this example). The
approximate position of the recording electrodes shown at
left, and distances in millimeters define electrode
position relative to stratum pyramidale. Note the increase in amplitude
of the stratum oriens potentials (but not stratum radiatum) as the oscillation develops. Recurrent synaptic connections between CA1
pyramidal cells are believed to be in stratum oriens (Deuchars and
Thomson, 1996).
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EPSPs synchronized with population spikes were shown previously to
occur in hyperpolarized pyramidal neurons during the oscillation
(Whittington et al., 1997b). Figure 5B provides additional evidence that these EPSPs represent a network phenomenon. In CA1, pyramidal cell pyramidal cell connections are believed to form predominantly in stratum oriens (Deuchars and Thomson, 1996). Figure 5B shows a transition in which
extracellular potentials were recorded simultaneously in stratum
pyramidale and stratum oriens, the recordings beginning immediately
after the stimulus artifacts. Note that most of the extracellular
potentials in stratum oriens increase in amplitude as the oscillation develops, whereas there is little activity in stratum
radiatum, during either the or phases. This experiment gave
similar results in three slices. These data suggest that the
increasing amplitude stratum oriens potentials are field EPSPs and the
extracellular correlates of the EPSPs recorded intracellularly during
the phase (Whittington et al., 1997b).
Effects of increasing gK(AHP)
or recurrent EPSPs, but not both together
In simulations, it is possible to manipulate, independently,
maximal gK(AHP) and unitary EPSC amplitude. In
Figure 6, the simulation of Figure 4 was
repeated, but over the 800-1200 msec interval after onset of the run
(shown by the ramp), unitary EPSCs (pyramidal/pyramidal) were increased
only twofold, instead of 4.6-fold, whereas maximal
gK(AHP) was increased fourfold, as before. In
the present case, individual pyramidal cell firing rates decrease to
the range (Fig. 6, top trace), at least transiently, but firing in the phase is not synchronized. This fact is indicated by
the population EPSPs in a hyperpolarized pyramidal cell, which are
about the same amplitude in the phase as in the phase, despite
the twofold increase in unitary EPSC amplitude (Fig. 6, middle
trace). In addition, pyramidal cells never fire spike doublets, because the second spike in a pyramidal doublet (in CA1) is recruited synaptically by the pyramidal cell population firing during the first spike, analogous to what happens with interneuron
doublets. Without pyramidal cell doublets in the phase,
interneurons continue to fire singlets and doublets and do not fire
bursts. These cellular behaviors do not correspond to experimental
/ shifts. The simulation of Figure 6, however, may capture what
happens as a oscillation breaks apart at the population level, when
an organized phase fails to occur.
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Figure 6.
When gK(AHP) increases
during the oscillation but EPSPs fail to develop, individual
pyramidal cells fire at frequencies, but asynchronously
(simulation). The simulation was identical to that of Figure 4, with
maximal gK(AHP) increasing fourfold over the
time interval 800-1200 msec (ramp), but in the present case, unitary
EPSCs only double over this time interval rather than increasing
4.6-fold. We again illustrate pyramidal cells (at x = 5, and a hyperpolarized one at x = 91), and a
basket cell. In the present case, individual pyramidal cell firing
slows once gK(AHP) has increased, and cells
"skip beats" of the underlying 33 Hz population rhythm. Because
pyramidal cells do not fire doublets in this case, interneurons do not
burst but instead fire singlets and doublets. These singlets and
doublets occur at frequency (albeit slower than the original frequency in the simulation, 52 Hz), and induce rhythmic synaptic
potentials in pyramidal cells.
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The data in Figure 6 suggest that sufficiently large AMPA
receptor-mediated, pyramidal/pyramidal EPSC increases are necessary for
a synchronized oscillation to develop. Whittington et al. (1997b)
used pressure ejection of NBQX to provide evidence that the phase
EPSCs are indeed dependent on AMPA receptors. One expects, therefore,
that pressure ejection of NBQX would also prevent a switch to a
synchronized oscillation from occurring, as measured with field
potential recordings. The data of Figure 7 indicate that this is indeed the case.
In experiments in six slices, / oscillations were evoked by
two-site twice-threshold stimuli under control conditions (Fig.
7A). Puffing on NBQX (20 µM,  ) midway
between the stimulation sites prevented an abrupt shift (Fig.
7B), although oscillation frequency does slow gradually, as
normally occurs with oscillations (Whittington et al., 1997b, their
Fig. 1Ba); oscillations were also prolonged in these instances, for
reasons that were not clear. Note as well that NBQX additionally increases oscillation frequency and disrupts two-site synchrony (cross-correlations in Fig. 7Aii,Bii), an effect predicted
by our model and previously shown experimentally (Whittington et al.,
1997a).
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Figure 7.
NBQX prevents the frequency shift.
Concurrent extracellular recordings (beginning immediately after the
stimulus artifact), from the same slice, with two-site twice-threshold
tetanic stimulation in each case. A, Control case. A transition occurs. Cross-correlation (below) of the first 200 msec of the oscillation shows tight synchrony (phase lag near 0)
and frequency 47 Hz. B, Puffing on NBQX (20 µM, ) at a site midway between sites 1 and 2 prevents
oscillation but not oscillation. For reasons that are not
clear, the oscillation is prolonged. [Note that NBQX in the bath
does eventually block tetanically induced oscillations (Whittington
et al., 1997a).] Consistent with previous results (Whittington et al.,
1997a), NBQX increases oscillation frequency (to 55 Hz) and increases
the two-site phase lag (to 5.6 msec).
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In comparing the simulation of Figure 6 with the experiments in Figure
7, it is important to note that the simulation shows the potentials of
individual cells, whereas the experiment is illustrated with field
potentials. Although individual cells in simulations slow their firing
rates to the range, this slower firingnot being synchronized,
when recurrent EPSPs are not enhanced enoughwould not be expected to
show up in field potential recordings. Only the synchronized oscillation would be expected to be manifest in field potential
recordings under such conditions.
In the case illustrated in Figure
8A, the simulation of
Figure 4 was repeated, but this time maximal
gK(AHP) was kept constant, whereas unitary
pyramidal/pyramidal EPSCs were increased 4.2-fold (a bit less than in
Fig. 4). The phase now resembles an epileptic afterdischarge, with
both pyramidal cells and interneurons firing in bursts at ~20 Hz in a
pattern not usually observed experimentally. -phase EPSPs in
hyperpolarized pyramidal cells, in the present case, have a duration of
almost 50 msec, but experimental -phase EPSPs can be almost this
broad (Whittington et al., 1997b). Similar afterdischarge-like firing
patterns were observed in two slices, although at lower frequency (~4
Hz) (Fig. 8B); however, we do not have data to show
that the repeating bursts resulted from a relative attenuation of AHP
conductances.
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Figure 8.
When EPSPs develop during the oscillation but
gK(AHP) fails to increase, synchronized
bursts occur. Similar behavior can be seen experimentally.
A, Simulation. The simulation was as in Figure 4, but
during the 800-1200 msec time interval (relative to the onset of the
run, ramp), maximum gK(AHP) remains constant
while unitary pyramidal/pyramidal EPSCs increase in amplitude 4.2-fold.
As usual, we illustrate two pyramidal cells [at x = 5, and a hyperpolarized one (3.0 nA current) at
x = 91] and a basket cell (x = 5). In the present case, the oscillation is succeeded by bursts, at
~20 Hz, in both pyramidal cells and interneurons. B,
Experiment. Simultaneous dual intracellular recordings (pyramidal
cells) and field potential showing transition from oscillation to
epileptic afterdischarge at ~4 Hz. Recordings begin immediately
after the stimulus artifact. The first 200 msec of activity was
synchronized between the two sites to within 1 msec.
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Persistent effects of twice-threshold tetanizations that
induce oscillations
Persistent synchrony
In Whittington et al. (1997b), it was shown that a single
administration of a twice-threshold stimulus (one that elicited a
oscillation) would alter circuit properties, so that later threshold stimuli would also each elicit a oscillation, stimuli of
intensity too weak to elicit a oscillation under control conditions. An example of this phenomenon with two-site stimulation, in
which tetanic stimuli were delivered to the two sites every 4 min, is
shown clearly in Figure 9. Under control
conditions (Fig. 9A), a threshold stimulus evoked activity only. When one delivery of twice-threshold stimulation was
administered simultaneously to both sites (Fig. 9B), a transition occurred. After this, later threshold
stimuli could now evoke transitions. This effect of
twice-threshold stimulation was observed in five slices.
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Figure 9.
Beta oscillation induced by two-site
twice-threshold stimulation recurs when two-site
threshold stimulation is later applied. Two-site field
potentials (recordings begin immediately after stimulus artifact) are
concurrent. Stimuli are given every 4 min. A, Two-site
threshold stimulus evokes oscillations only. B,
Two-site twice-threshold stimulus evokes transition.
C, Later two-site threshold stimulus now evokes transition. [Repeating threshold stimuli by themselves do not
elicit transitions (Whittington et al., 1997b).]
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We should note as well that a single administration of a two-site
twice-threshold stimulus also produces long-lasting changes in
recurrent CA1 pyramidal cell pyramidal cell excitatory synaptic connections. This was shown by Whittington et al. (1997b), who observed
that pairs of pyramidal cells existed with these properties: (1) under
control conditions, spikes in cell 1 failed to elicit EPSPs in cell 2;
(2) during an oscillation evoked by two-site twice-threshold
stimulation, spikes in cell 1 did elicit EPSPs in cell 2;
and (3) during later oscillations, evoked by threshold stimuli, spikes in cell 1 still elicited EPSPs in cell 2. The data presented so far suggest that persistent effects on EPSPs and
on oscillations are causally related (see Discussion).
A mechanism for desynchronizing oscillations at the
two sites
How can one account for a type of |
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Abstract
Introduction
