 |
 Previous Article | Next Article 
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
 |
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
| |
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.
| |
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).
View larger version (18K):
[in this window]
[in a new window]
|
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.
|
|
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.)
| |
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.
View larger version (26K):
[in this window]
[in a new window]
|
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).
|
|
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.
View larger version (42K):
[in this window]
[in a new window]
|
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.
|
|
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.
View larger version (35K):
[in this window]
[in a new window]
|
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).
|
|
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).
View larger version (36K):
[in this window]
[in a new window]
|
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).
|
|
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.
View larger version (46K):
[in this window]
[in a new window]
|
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.
|
|
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).
View larger version (21K):
[in this window]
[in a new window]
|
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).
|
|
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.
View larger version (48K):
[in this window]
[in a new window]
|
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.
|
|
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.
View larger version (27K):
[in this window]
[in a new window]
|
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).]
|
|
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 synchrony modulation that is
converse to the one described above (the enhancement of synchrony after two-site twice-threshold stimulation)? That is, we must explain
why, after a single episode of one-site twice-threshold tetanus, oscillations subsequently evoked by two-site
threshold tetani do not synchronize between the two sites (Whittington
et al., 1997b). One possibility considered by Whittington et al. (1997b) was that the one-site twice-threshold stimulus induced strong
enough recurrent, pyramidal/pyramidal EPSPs that pyramidal cell spike
doublets would occur in the phase of subsequent oscillations. Pyramidal cell doublets in the intensely stimulated site, but not in
the other site, would prevent synchrony, because the two sites would
"try" to oscillate at different frequencies, the site with doublets
oscillating more slowly. This explanation, however, appears unlikely
for two reasons: (1) pyramidal cell doublets are rarely observed during
CA1 oscillations, even after a strong tetanus [although such
doublets do occur in subiculum, wherein intrinsic cell properties
contribute (Stanford et al., 1998)], and (2) EPSPs usually do not
occur in pyramidal cells until toward the end of the phase of the oscillation.
An alternative possible explanation is that one-site
twice-threshold tetanic stimulation induces persistent depression of long-range pyramidal interneuron synapses (depression of long-range pyramidal pyramidal synapses in CA1 would not be expected to influence synchrony, because EPSPs are not well developed during in any case). The idea is that depression of long-range pyramidal interneuron synapses, if sufficiently developed, would suppress interneuron doublets (Fig. 2) (Traub et al., 1996a,b;
Whittington et al., 1997a) and so prevent long-range synchrony.
The simulation in Figure 10 illustrates
this possibility. Parameters were chosen such that a globally
synchronized oscillation would occur, as in the phase of Figure
4 (maximal gK(AHP) 0.25 × its standard
value, unitary pyramidal/pyramidal EPSC 0.75 × t × et/2 nS), but the simulation was
performed with a change in the synaptic excitation of interneurons:
pyramidal interneuron connections, in which presynaptic and
postsynaptic cells were on opposite sides of the array, had their
maximum conductance reduced by 90%. This prevented interneuron
doublets, and the mean phase lag between the two sides increased from
1.7 msec (control conditions) to 5.6 msec (when long-range pyramidal
cell interneuron connections were depressed).
View larger version (34K):
[in this window]
[in a new window]
|
Figure 10.
Blockade of long-range pyramidal cell interneuron synaptic interactions prevents interneuron spike doublets,
and hence two-site synchronization cannot occur (simulation). Network
parameters were the same as for the phase of Figure 4 (maximal
gK(AHP) 0.25 × its standard value,
unitary pyramidal/pyramidal EPSC 0.75 × t × et/2 nS), with this
exception: for any pyramidal cell interneuron connection that
crosses the array midline in either direction, the corresponding
unitary EPSC takes on one-tenth of its usual amplitude (2.0 × t × et nS). As
usual, we illustrate two pyramidal cells (at x = 5, and a hyperpolarized one at x = 91) and a basket
cell (x = 5). A, Because the AMPA
receptor-mediated input to interneurons is close to the input that
would occur with single-site stimulation [Fig. 2 and Traub et al.
(1996a,b)], interneurons do not fire doublets. B, As a
consequence, the two sides of the array do not oscillate synchronously
(cross-correlation peak at 5.6 msec). Autocorrelation and
cross-correlation of e-cell average signals are shown.
|
|
Experimentally, it was possible to record from two interneurons long
enough to test portions of this hypothesis. An example is shown in
Figure 11. In each case, the field
potential was recorded near site 1, while an interneuron was
recorded intracellularly near site 2. A control two-site threshold
tetanic stimulation evoked a oscillation of declining frequency,
with interneuron singlets and doublets (Fig. 11A).
Cross-correlation of the initial portion of this oscillation (field vs
interneuron) produced an inverted peak at 2.0 msec (the "peak" is
negative because the two signals have opposite signs). Four oscillatory
episodes were then evoked by stimulating site 1 with twice-threshold
intensity, recording meanwhile from the interneuron at site 2 while the
latter was hyperpolarized to 80 mV (near GABAA receptor
reversal potential) by passage of current through the electrode. The
oscillatory episodes were 4 min apart, and three of them are shown in
Figure 11B. What is clear is that each successive
site 1 oscillation is associated with less excitatory synaptic activity
in the interneuron. (The depolarizing potentials in the interneuron are
unlikely to be reversed IPSPs, because the tetanus was delivered to the
opposite site, >1.5 mm away, and it is at this distant site where
interneurons would be firing.) After these four oscillatory episodes, a
repeat two-site threshold tetanic stimulus failed to evoke interneuron doublets (Fig. 11C). Loss of interneuron doublets was
observed as late as 8 min after the last one-site twice-threshold
stimulus to the opposite site, after which the cell was lost.
Furthermore, the cross-correlation signal (Fig. 11C,
right), although it has an inverted peak at 2 msec, is
disorganized. This occurs because of varying phase relations between
successive interneuron spikes/population spikes.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 11.
After twice-threshold
stimulation-induced oscillations at one site, EPSPs are
reduced in an interneuron at the other site, and subsequent two-site
tetanic stimuli do not lead to interneuron doublets. All recordings are
from the same slice, with an extracellular (ec)
recording electrode at site 1 and an intracellular recording of an
interneuron at site 2 (same cell throughout the figure). Signals begin
just after stimulus artifacts. A, oscillation
induced by two-site threshold stimulation. Note the interneuron
doublets. Cross-correlation of the two signals produces a
negative-going "peak" (because one signal is upgoing and the other
downgoing) at 2 msec. B, The interneuron at site 2 was
hyperpolarized to 80 mV, near GABAA reversal potential,
by passage of 0.3 nA current. Successive oscillations induced by
twice-threshold stimulation of the opposite site lead to EPSPs in the
interneuron that were of reduced amplitude and frequency.
C, A subsequent two-site threshold tetanus-evoked
oscillation is no longer associated with interneuron doublets. The
variable phase relations of population spikes and action potentials
leads to a disorganized appearance of the cross-correlation
(right).
|
|
A quantitative summary of the data for EPSPs in the two interneurons,
for the first 200 msec of oscillations evoked by twice-threshold stimulation of the opposite site, is as follows. For the first interneuron, there were 12 EPSPs of amplitude 2.4 ± 0.2 mV (SEM) at 0 min, six EPSPs of amplitude 2.2 ± 1.0 mV at 4 min, and nine EPSPs of amplitude 1.4 ± 0.5 mV at 8 min. For the second
interneuron, there were seven EPSPs of amplitude 3.6 ± 0.4 mV at
0 min, eight EPSPs of amplitude 2.1 ± 0.6 mV at 4 min, and six
EPSPs of amplitude 1.7 ± 0.6 mV at 8 min. In each case, the
decline in mean amplitude between 0 and 8 min was statistically
significant (p < 0.05, nonpaired t test).
| |
DISCUSSION |
There are two main results in this paper. First, - and
-frequency oscillations, induced by tetanic stimulation of the CA1 region in vitro, are synchronized by different cellular
mechanisms. IPSPs are critical for shaping [because
GABAA receptor blockade abolishes the oscillation
(Whittington et al., 1995; Colling et al., 1998)], and EPSPs onto
interneurons are necessary for long-range synchrony (Traub et al.,
1996a,b; Whittington et al., 1997a), but EPSPs between pyramidal cells
within CA1, so far as we can tell, do not play an essential role in oscillations. In contrast, EPSPs between CA1 pyramidal cells do appear
to be critical for generating a synchronized rhythm, even within a
local population of neurons, although such EPSPs may not be necessary
for individual pyramidal cells to fire at frequency
(Fig. 6).
Second, the contrasting cellular mechanisms of and oscillations
allow synaptic plasticity to regulate long-range synchrony of the two
frequency ranges by different means.
To make sense of these results, we first briefly review the cellular
mechanisms of and (induced by tetanic stimulation in CA1),
according to our present notions.
Mechanisms of oscillations, tetanically induced in CA1
One can view the structure of in three levels of complexity.
(1) Pharmacologically isolated networks of interneurons, when tonically
excited, can produce locally synchronized oscillations, dependent
on i i synaptic interactions (GABAA receptors), and with frequency dependent on "drive" to the interneurons and the parameters of the i i IPSCs (Whittington et al., 1995; Traub et
al., 1996b). This type of oscillation appears to be incapable of
maintaining synchrony over distances more than ~1 mm (Whittington et
al., 1997a).
(2) Local networks of pyramidal cells and interneurons can also
generate locally synchronized oscillations ["local" means "on a distance scale of about 400 µm" (Colling et al., 1998)]. In this case, interneurons and pyramidal cells fire in phase, to within
a couple of milliseconds, and both pyramidal cells and interneurons
fire in singlets (Traub et al., 1996a; Whittington et al., 1997a).
Oscillation frequency can be modified by driving currents to the
pyramidal cells alone, at least in simulations, as well as by IPSC
parameters (Traub et al., 1997; Whittington et al., 1998).
(3) Distributed (i.e., on a spatial scale more than ~1 mm) networks
of pyramidal cells and interneurons can also generate synchronized oscillations. The interneurons (stratum pyramidale and stratum oriens)
often fire in doublets, and the pyramidal cell spikes and the first
spike of the interneuron doublet are nearly in phase. Pyramidal cell
spikes and the first spike of the interneuron arise from tonic driving
conductances to the respective cell types, with timing gated by IPSPs.
Because both pyramidal cells and interneurons "see" the "same"
IPSPs, it makes sense that the two cell types fire nearly in phase.
The second spike in the interneuron doublet arises from the AMPA
receptor-mediated synaptic input generated by the synchronized
pyramidal cell spike. Experiments, simulation studies, and mathematical
analysis suggest that interneuron doublet-firing is
necessary for long-range synchrony under these conditions
and is not an epiphenomenon (Whittington et al., 1997a; Ermentrout and
Kopell, 1998).
The role of interneuron-interneuron IPSPs in cases (2) and (3), when
pyramidal cells are firing in addition to interneurons, is not clear.
The issue is difficult to examine experimentally, because one is
required to block GABAA IPSCs selectively on interneurons and not on pyramidal cells, a problem that may require transgenic techniques. The mathematical model of Ermentrout and Kopell (1998) does not require interneuron-interneuron IPSPs.
Similarly, pyramidal-pyramidal EPSPs are not required in simulation
models of CA1 oscillations. Simulations indeed indicate that such
EPSPs, if present at large enough amplitude, will lead to pyramidal
cell doublets (rarely observed experimentally during ) or to bursts
(Traub et al., 1997; Whittington et al., 1997b). On the other hand, we
do not have experimental data from paradigms in which EPSPs are
selectively blocked on pyramidal cells and not on interneurons.
Mechanisms of oscillations, tetanically induced
in CA1
After tetanic stimulation powerful enough to produce a switch, three experimental observations are salient. (1) Intracellular depolarizations are sustained during the phase, both in pyramidal cells (Whittington et al., 1997b) and in interneurons (present observations), and (2) pyramidal cell fast-spike AHPs, which
virtually vanish during the phase, recover before and during the
phase (Whittington et al., 1997b). Presumably, slower
Ca2+-dependent AHPs, which would also be blocked by
metabotropic glutamate receptor activation (Charpak and Gähwiler,
1991), recover as well, before and during the phase, but we do not
have direct experimental evidence for this. (3) AMPA receptor-mediated
EPSPs develop in pyramidal cells before and during the phase.
By increasing the conductance of Ca2+-dependent AHPs
alone, our present simulations indicate that observations (1) and (2)
account for the slowing of individual pyramidal cell firings to frequency (Fig. 6). The reason is that the interneuron network
continues to oscillate synchronously at frequency, producing
-frequency IPSPs in pyramidal cells, but the pyramidal cells, whose
membranes are now more shunted, are unable to fire on each wave.
Because the pyramidal cells are not driven with identical tonic
conductances, each pyramidal cell is free to develop its own pattern of
wave-skipping, so that the oscillation will not synchronize. For
this mechanism to operate in a stable manner, interneuron-interneuron
IPSPs may possibly be required, but we have not examined this issue in
detail. The recovery of K conductances with faster kinetics than the
AHP conductance would be expected (1) to have either little effect on
oscillations, if the kinetics is fast relative to the
40-100 msec period of waves or (2) to reinforce the effects of
recovery of the AHP conductance, by reducing the ability of pyramidal
cells to fire on each wave. It is possible that a time-dependent
increase in membrane leak conductance could exert a functional effect
similar to that of an increase in the slow AHP conductance.
On the other hand, when EPSPs between pyramidal cells of sufficient
strength are added, then pyramidal cells interact with each other
directly. The firing of some pyramidal cells on a particular wave
will tend to induce the firing of other pyramidal cells on that same
wave. Because AHPs remain large, however, each individual pyramidal
cell still can fire only at frequency; it cannot, in general, fire
on every wave (Figs. 4, 5).
A by-product of this arrangement is that some pyramidal cells, being
recurrently excited, will fire in doublets, whereas interneurons, being
excited by pyramidal cell doublets, may sometimes fire in brief bursts
(Figs. 4, 5).
An experimental prediction of this idea is that blockade of recurrent
excitation, mediated by AMPA receptors, should prevent a synchronized
oscillation, and this occurs (Fig. 7). Unfortunately, the drug used
in this experiment, NBQX, also blocks AMPA receptors on interneurons.
oscillations can occur, however, after joro toxin application (Fig.
3Bi), which blocks certain interneuron AMPA receptors. It
therefore appears likely that NBQX prevents the occurrence of oscillations via a blockade of AMPA receptors at pyramidal cell pyramidal cell synaptic connections.
Strong tetanic stimulation, synaptic plasticity, and
long-range synchronization
Cortical structures viewed as interconnected oscillating
neuronal ensembles
A commonly held view of the cortex might be characterized as
follows. The computing units are single neurons, and information is
stored, in a distributed manner, by modifying synaptic strengths (predominantly at pyramidal cell/pyramidal cell synapses) in a "Hebbian" manner, that is, dependent on the history of the
correlations between presynaptic and postsynaptic activities.
The data on plasticity of and oscillations are most readily
interpreted within an alternative framework, the validity of which
needs further investigation. Cortical structures, at least during
certain states, consist of a collection of oscillating neuronal
ensembles (Sompolinsky et al., 1990; Palm, 1982). These ensembles
(which in our experiments would contain 1000 or 2000 neurons) can
oscillate in synchrony or out of synchrony with each other, and
information is stored in groups of synapses that
interconnect the ensembles and determine whether synchronization is to
occur in a particular band of frequencies.
Long-range synchronization of
A two-site twice-threshold tetanus, given only one time, induces
synchronized and oscillations "acutely" (i.e., with onset tens of milliseconds after the stimulus); additionally, such a stimulus
allows a later two-site threshold tetanus to induce
synchronized and oscillations (Fig. 9) (Whittington et al.,
1997b). [Under control conditions, threshold-intensity tetani at two
sites do not lead to synchronized oscillations (Fig. 9).] The
long-lasting (tens of minutes, at least) inducibility of synchronized
oscillations can be explained, according to our present results, by
the fact that the EPSPs associated with the oscillation recur after
threshold stimuli-induced oscillations, once these EPSPs have been
induced by a twice-threshold stimulus (Whittington et al., 1997b),
provided that the augmented EPSPs reflect functional recurrent
connections between nearby as well as distant pyramidal cells.
Long-range desynchronization of
A twice-threshold tetanus delivered to one site rather
than two has desynchronizing effects on two-site-stimulated
(threshold intensity stimuli), as opposed to the
synchronizing effects of strong two-site tetanus
on two-site-stimulated (Whittington et al., 1997b).
Because interneuron doublets are necessary for long-range synchrony of
tetanically induced oscillations, loss of interneuron doublets
might explain desynchronization. Interneuron doublets would
disappearso far as interneurons were concernedif two-site stimulation were indistinguishable from one-site stimulation [Fig. 2
and Traub et al. (1996a,b)], and this situation would exist if
single-site 2×T stimulation were to cause depression of long-range pyramidal cell interneuron connections. This scheme does indeed cause two-site desynchronization in simulations (Fig. 10).
Furthermore, experimental data indicate that one-site 2×T tetanization
leads to a loss of interneuron doublets (Fig. 11) when
subsequent two-site threshold stimuli are delivered, stimuli
that normally would cause interneuron doublets in at least some cells
[Fig. 11 and Whittington et al. (1997a)].
Why might depression of long-range pyramidal cell interneuron
connections occur after a strong tetanus to a single site, say site 1?
Following standard "Hebbian" ideas on LTP and LTD, let
e1 and e2 denote pyramidal cells at sites 1 and
2, respectively, and i1 and i2 denote
interneurons at sites 1 and 2, respectively. A strong tetanus to site 1 would be expected to cause intense firing of e1 and
i1 but much less intense firing of e2 and
i2. Under such conditions, both e1 i2 and e2 i1 would be expected to depress. Our data (Fig. 11) suggest that depression of
e1 i2 should occur, but we have no
information about e2 i1 or about e1 i1. The experimental evidence also
supports a secondary consequence of the presumed long-range synaptic
depression: loss of interneuron doublets at the site opposite to the
stimulated site. Again, we have no information concerning altered
firing behavior in interneurons near to the stimulated site. With
two-site stimulation, pyramidal cells and interneurons at both sites
would be firing at high rates while also receiving synaptic excitation
at high rates. One would not expect synaptic depression under these conditions.
In conclusion, oscillations elicited by tetanic stimulation of CA1
in vitro are organized and synchronized by IPSPs and by AMPA
receptors on interneurons. oscillations occur superimposed on oscillations in interneuron networks: pyramidal cells do not fire on
each wave, and mutual EPSPs ensure that different pyramidal cells
fire on the same waves. The distinctive structure of the two sorts
of oscillation provide different possible mechanisms for synaptic
plasticity to modulate synchronization.
More speculatively, we might suggest the following. Suppose it is true
that oscillations are critical for perception, the detailed percept
depending on which neurons oscillate in phase with each other. The
occurrence of oscillations might, perhaps as a "flag," reflect
the occurrence of a percept of particular novelty or significance,
which at the cellular level would require sufficient activation of
metabotropic receptors. Once such activation has occurred, the neuronal
circuitry will have been modified (i.e., a memory will have been
formed). The memory is "read" by the future expression of
oscillation-synchronization, either in or in frequencies or
both. Note that what is here called "" is 10-25 Hz, a band that
overlaps the  range of human EEG nomenclature. In human studies,
with use of electroencephalographic and magnetoencephalographic data
supplemented with other techniques that come along in future, the
relations between waves and immediately succeeding slower waves
will prove interesting.
| |
FOOTNOTES |
Received Aug. 31, 1998; revised Oct. 28, 1998; accepted Nov. 13, 1998.
This work was supported by the Wellcome Trust, the Medical Research
Council (United Kingdom), and the Human Frontier Science Program.
R.D.T. is a Wellcome Principal Research Fellow. We acknowledge helpful
discussions with Nancy Kopell, Bard Ermentrout, Hannah Monyer, and
Andrea Bibbig.
Correspondence should be addressed to R. D. Traub, Division of
Neuroscience, University of Birmingham School of Medicine, Edgbaston,
Birmingham B15 2TT, UK.
| |
REFERENCES |
-
Barth DS,
MacDonald KD
(1996)
Thalamic modulation of high-frequency oscillating potentials in auditory cortex.
Nature
383:78-81[Medline].
-
Buhl EH,
Halasy K,
Somogyi P
(1994a)
Diverse sources of hippocampal unitary inhibitory postsynaptic potentials and the number of synaptic release sites.
Nature
368:823-828[Medline].
-
Buhl EH,
Han Z-S,
Lörinczi Z,
Stezhka VV,
Karnup SV,
Somogyi P
(1994b)
Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus.
J Neurophysiol
71:1289-1307[Abstract/Free Full Text].
-
Charpak S,
Gähwiler BH
(1991)
Glutamate mediates a slow synaptic response in hippocampal slice cultures.
Proc R Soc Lond B Biol Sci
243:221-226[Medline].
-
Charpak S,
Gähwiler BH,
Do KQ,
Knöpfel T
(1990)
Potassium conductances in hippocampal neurons blocked by excitatory amino acid transmitters.
Nature
347:765-767[Medline].
-
Colling SB,
Stanford IM,
Traub RD,
Jefferys JGR
(1998)
Limbic gamma rhythms. I. Phase-locked oscillations in hippocampal CA1 and subiculum.
J Neurophysiol
80:155-161[Abstract/Free Full Text].
-
Deuchars J,
Thomson AM
(1996)
CA1 pyramid-pyramid connections in rat hippocampus in vitro: dual intracellular recordings with biocytin filling.
Neuroscience
74:1009-1018[Web of Science][Medline].
-
Ermentrout GB,
Kopell N
(1998)
Fine structure of neural spiking and synchronization in the presence of conduction delays.
Proc Natl Acad Sci USA
95:1259-1264[Abstract/Free Full Text].
-
Geiger JRP,
Melcher T,
Koh D-S,
Sakmann B,
Seeburg PH,
Jonas P,
Monyer H
(1995)
Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS.
Neuron
15:193-204[Web of Science][Medline].
-
Glaze DG
(1990)
Drug effects.
In: Current practice of clinical electroencephalography, ed 2 (Daly DD,
Pedley TA,
eds), pp 489-512. New York: Raven.
-
Gray CM
(1994)
Synchronous oscillations in neuronal systems: mechanisms and functions.
J Comput Neurosci
1:11-38[Medline].
-
Guérineau NC,
Bossu J-L,
Gähwiler BH,
Gerber U
(1995)
Activation of a nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus.
J Neurosci
15:4395-4407[Abstract].
-
Halasy K,
Buhl EH,
Lörinczi Z,
Tamás G,
Somogyi P
(1996)
Synaptic target selectivity and input of GABAergic basket and bistratified interneurons in the CA1 area of the rat hippocampus.
Hippocampus
6:306-329[Web of Science][Medline].
-
Iino M,
Koike M,
Isa T,
Ozawa S
(1996)
Voltage-dependent blockage of Ca2+-permeable AMPA receptors by joro spider toxin in cultured rat hippocampal neurones.
J Physiol (Lond)
496:431-437[Abstract/Free Full Text].
-
König P,
Engel AK,
Singer W
(1996)
Integrator or coincidence detector? The role of the cortical neuron revisited.
Trends Neurosci
19:130-137[Web of Science][Medline].
-
Leung LS
(1992)
Fast (beta) rhythms in the hippocampus: a review.
Hippocampus
2:93-98[Web of Science][Medline].
-
McHugh TJ,
Blum KI,
Tsien JZ,
Tonegawa S,
Wilson MA
(1996)
Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice.
Cell
87:1339-1349[Web of Science][Medline].
-
Murthy VN,
Fetz EE
(1992)
Coherent 25- to 35-Hz oscillations in the sensorimotor cortex of awake behaving monkeys.
Proc Natl Acad Sci USA
89:5670-5674[Abstract/Free Full Text].
-
Palm G
(1982)
In: Neural assemblies. An alternative approach to artificial intelligence. Berlin: Springer.
-
Pantev C
(1995)
Evoked and induced gamma-band activity of the human cortex.
Brain Topogr
7:321-330[Medline].
-
Pearce RA
(1993)
Physiological evidence for two distinct GABAA responses in rat hippocampus.
Neuron
10:189-200[Web of Science][Medline].
-
Ribary U,
Ioannides AA,
Singh KD,
Hasson R,
Bolton JPR,
Lado F,
Mogilner A,
Llinás R
(1991)
Magnetic field tomography of coherent thalamocortical 40-Hz oscillations in humans.
Proc Natl Acad Sci USA
88:11037-11041[Abstract/Free Full Text].
-
Roelfsema PR,
Engel AK,
König P,
Singer W
(1997)
Visuomotor integration is associated with zero time-lag synchronization among cortical areas.
Nature
385:157-161[Medline].
-
Salin PA,
Prince DA
(1996)
Electrophysiological mapping of GABAA receptor-mediated inhibition in adult rat somatosensory cortex.
J Neurophysiol
75:1589-1600[Abstract/Free Full Text].
-
Sik A,
Penttonen M,
Ylinen A,
Buzsáki G
(1995)
Hippocampal CA1 interneurons: an in vivo intracellular labeling study.
J Neurosci
15:6651-6665[Abstract/Free Full Text].
-
Singer W,
Gray CM
(1995)
Visual feature integration and the temporal correlation hypothesis.
Annu Rev Neurosci
18:555-586[Web of Science][Medline].
-
Sompolinsky H,
Golomb D,
Kleinfeld D
(1990)
Global processing of visual stimuli in a neural network of coupled oscillators.
Proc Natl Acad Sci USA
87:7200-7204[Abstract/Free Full Text].
-
Stanford IM,
Traub RD,
Jefferys JGR
(1998)
Limbic gamma rhythms. II. Synaptic and intrinsic mechanisms underlying spike doublets in oscillating subicular neurons.
J Neurophysiol
80:162-171[Abstract/Free Full Text].
-
Steriade M,
Amzica F
(1996)
Intracortical and corticothalamic coherency of fast spontaneous oscillations.
Proc Natl Acad Sci USA
93:2533-2538[Abstract/Free Full Text].
-
Steriade M,
Timofeev I,
Dürmüller N,
Grenier F
(1998)
Dynamic properties of corticothalamic neurons and local cortical interneurons generating fast rhythmic (30-40 Hz) spike bursts.
J Neurophysiol
79:483-490[Abstract/Free Full Text].
-
Tamamaki N,
Nojyo Y
(1990)
Disposition of the slab-like modules formed by axon branches originating from single CA1 pyramidal neurons in the rat hippocampus.
J Comp Neurol
291:509-519[Web of Science][Medline].
-
Traub RD,
Miles R
(1991)
In: Neuronal networks of the hippocampus. Cambridge, UK: Cambridge UP.
-
Traub RD,
Miles R
(1995)
Pyramidal cell-to-inhibitory cell spike transduction explicable by active dendritic conductances in inhibitory cell.
J Comput Neurosci
2:291-298[Web of Science][Medline].
-
Traub RD,
Wong RKS,
Miles R,
Michelson H
(1991)
A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances.
J Neurophysiol
66:635-650[Abstract/Free Full Text].
-
Traub RD,
Miles R,
Jefferys JGR
(1993)
Synaptic and intrinsic conductances shape picrotoxin-induced synchronized after-discharges in the guinea-pig hippocampal slice.
J Physiol (Lond)
461:525-547[Abstract/Free Full Text].
-
Traub RD,
Jefferys JGR,
Miles R,
Whittington MA,
Tóth K
(1994)
A branching dendritic model of a rodent CA3 pyramidal neurone.
J Physiol (Lond)
481:79-95[Abstract/Free Full Text].
-
Traub RD,
Colling SB,
Jefferys JGR
(1995)
Cellular mechanisms of 4-aminopyridine-induced synchronized after-discharges in the rat hippocampal slice.
J Physiol (Lond)
489:127-140[Abstract/Free Full Text].
-
Traub RD,
Whittington MA,
Colling SB,
Buzsáki GB,
Jefferys JGR
(1996a)
Analysis of gamma rhythms in the rat hippocampus in vitro and in vivo.
J Physiol (Lond)
492:471-484.
-
Traub RD,
Whittington MA,
Stanford IM,
Jefferys JGR
(1996b)
A mechanism for generation of long-range synchronous fast oscillations in the cortex.
Nature
383:621-624[Medline].
-
Traub RD,
Jefferys JGR,
Whittington MA
(1997)
Simulation of gamma rhythms in networks of interneurons and pyramidal cells.
J Comput Neurosci
4:141-150[Web of Science][Medline].
-
Wang X-J,
Buzsáki G
(1996)
Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model.
J Neurosci
16:6402-6413[Abstract/Free Full Text].
-
White JA,
Chow CC,
Ritt J,
Soto-Treviño C,
Kopell N
(1998)
Synchro-nization and oscillatory dynamics in heterogeneous, mutually inhibited neurons.
J Comput Neurosci
5:5-16[Web of Science][Medline].
-
Whittington MA,
Traub RD,
Jefferys JGR
(1995)
Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation.
Nature
373:612-615[Medline].
-
Whittington MA,
Stanford IM,
Colling SB,
Jefferys JGR,
Traub RD
(1997a)
Spatiotemporal patterns of frequency oscillations tetanically induced in the rat hippocampal slice.
J Physiol (Lond)
502:591-607[Abstract/Free Full Text].
-
Whittington MA,
Traub RD,
Faulkner HJ,
Stanford IM,
Jefferys JGR
(1997b)
Recurrent excitatory postsynaptic potentials induced by synchronized fast cortical oscillations.
Proc Natl Acad Sci USA
94:12198-12203[Abstract/Free Full Text].
-
Whittington MA,
Traub RD,
Faulkner HJ,
Jefferys JGR,
Chettiar K
(1998)
Morphine disrupts long-range synchrony of gamma oscillations in hippocampal slices.
Proc Natl Acad Sci USA
95:5807-5811[Abstract/Free Full Text].
Copyright © 1999 Society for Neuroscience 0270-6474/99/1931088-18$05.00/0
This article has been cited by other articles:
|
|
|
|
 
C. B. McCracken and A. A. Grace
Nucleus Accumbens Deep Brain Stimulation Produces Region-Specific Alterations in Local Field Potential Oscillations and Evoked Responses In Vivo
J. Neurosci.,
April 22, 2009;
29(16):
5354 - 5363.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bazhenov, N. F. Rulkov, and I. Timofeev
Effect of Synaptic Connectivity on Long-Range Synchronization of Fast Cortical Oscillations
J Neurophysiol,
September 1, 2008;
100(3):
1562 - 1575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Thaker
Neurophysiological Endophenotypes Across Bipolar and Schizophrenia Psychosis
Schizophr Bull,
July 1, 2008;
34(4):
760 - 773.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. G. Sannita, S. Carozzo, M. Fioretto, S. Garbarino, and C. Martinoli
Abnormal Waveform of the Human Pattern VEP: Contribution from Gamma Oscillatory Components
Invest. Ophthalmol. Vis. Sci.,
October 1, 2007;
48(10):
4534 - 4541.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bibbig, S. Middleton, C. Racca, M. J. Gillies, H. Garner, F. E. N. LeBeau, C. H. Davies, and M. A. Whittington
Beta Rhythms (15-20 Hz) Generated by Nonreciprocal Communication in Hippocampus
J Neurophysiol,
April 1, 2007;
97(4):
2812 - 2823.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Labyt, L. Uva, M. de Curtis, and F. Wendling
Realistic Modeling of Entorhinal Cortex Field Potentials and Interpretation of Epileptic Activity in the Guinea Pig Isolated Brain Preparation
J Neurophysiol,
July 1, 2006;
96(1):
363 - 377.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Nerad and D. K. Bilkey
Ten- to 12-Hz EEG Oscillation in the Rat Hippocampus and Rhinal Cortex That Is Modulated by Environmental Familiarity
J Neurophysiol,
March 1, 2005;
93(3):
1246 - 1254.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Vreugdenhil, E. Bracci, and J. G. R. Jefferys
Layer-specific pyramidal cell oscillations evoked by tetanic stimulation in the rat hippocampal area CA1 in vitro and in vivo
J. Physiol.,
January 1, 2005;
562(1):
149 - 164.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Traub, E. H. Buhl, T. Gloveli, and M. A. Whittington
Fast Rhythmic Bursting Can Be Induced in Layer 2/3 Cortical Neurons by Enhancing Persistent Na+ Conductance or by Blocking BK Channels
J Neurophysiol,
February 1, 2003;
89(2):
909 - 921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kubota, L. L. Colgin, M. Casale, F. A. Brucher, and G. Lynch
Endogenous Waves in Hippocampal Slices
J Neurophysiol,
January 1, 2003;
89(1):
81 - 89.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Mikkonen, T. Gronfors, J. J. Chrobak, and M. Penttonen
Hippocampus Retains the Periodicity of Gamma Stimulation In Vivo
J Neurophysiol,
November 1, 2002;
88(5):
2349 - 2354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. C. Stacey and D. M. Durand
Noise and Coupling Affect Signal Detection and Bursting in a Simulated Physiological Neural Network
J Neurophysiol,
November 1, 2002;
88(5):
2598 - 2611.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bibbig, R. D. Traub, and M. A. Whittington
Long-Range Synchronization of gamma and beta Oscillations and the Plasticity of Excitatory and Inhibitory Synapses: A Network Model
J Neurophysiol,
October 1, 2002;
88(4):
1634 - 1654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. E N LeBeau, S. K Towers, R. D Traub, M. A Whittington, and E. H Buhl
Fast network oscillations induced by potassium transients in the rat hippocampus in vitro
J. Physiol.,
July 1, 2002;
542(1):
167 - 179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Contreras and R. Llinas
Voltage-Sensitive Dye Imaging of Neocortical Spatiotemporal Dynamics to Afferent Activation Frequency
J. Neurosci.,
December 1, 2001;
21(23):
9403 - 9413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Traub, N. Kopell, A. Bibbig, E. H. Buhl, F. E. N. LeBeau, and M. A. Whittington
Gap Junctions between Interneuron Dendrites Can Enhance Synchrony of Gamma Oscillations in Distributed Networks
J. Neurosci.,
December 1, 2001;
21(23):
9478 - 9486.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bibbig, H. J. Faulkner, M. A. Whittington, and R. D. Traub
Self-Organized Synaptic Plasticity Contributes to the Shaping of gamma and beta Oscillations In Vitro
J. Neurosci.,
November 15, 2001;
21(22):
9053 - 9067.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Munera, A. Gruart, M. D. Munoz, R. Fernandez-Mas, and J. M. Delgado-Garcia
Hippocampal Pyramidal Cell Activity Encodes Conditioned Stimulus Predictive Value During Classical Conditioning in Alert Cats
J Neurophysiol,
November 1, 2001;
86(5):
2571 - 2582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bracci, M. Vreugdenhil, S. P. Hack, and J. G. R. Jefferys
Dynamic Modulation of Excitation and Inhibition During Stimulation at Gamma and Beta Frequencies in the CA1 Hippocampal Region
J Neurophysiol,
June 1, 2001;
85(6):
2412 - 2422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. C. Fuchs, H. Doheny, H. Faulkner, A. Caputi, R. D. Traub, A. Bibbig, N. Kopell, M. A. Whittington, and H. Monyer
Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation
PNAS,
March 13, 2001;
98(6):
3571 - 3576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Traub, R. Bibbig, A. Piechotta, R. Draguhn, and D. Schmitz
Synaptic and Nonsynaptic Contributions to Giant IPSPs and Ectopic Spikes Induced by 4-Aminopyridine in the Hippocampus In Vitro
J Neurophysiol,
March 1, 2001;
85(3):
1246 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Whittington, H. C. Doheny, R. D. Traub, F. E. N. LeBeau, and E. H. Buhl
Differential Expression of Synaptic and Nonsynaptic Mechanisms Underlying Stimulus-Induced Gamma Oscillations In Vitro
J. Neurosci.,
March 1, 2001;
21(5):
1727 - 1738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shimono, F. Brucher, R. Granger, G. Lynch, and M. Taketani
Origins and Distribution of Cholinergically Induced beta Rhythms in Hippocampal Slices
J. Neurosci.,
November 15, 2000;
20(22):
8462 - 8473.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Haenschel, T. Baldeweg, R. J. Croft, M. Whittington, and J. Gruzelier
Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models
PNAS,
June 13, 2000;
(2000)
120162397.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. D. Traub and A. Bibbig
A Model of High-Frequency Ripples in the Hippocampus Based on Synaptic Coupling Plus Axon-Axon Gap Junctions between Pyramidal Neurons
J. Neurosci.,
March 15, 2000;
20(6):
2086 - 2093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Smirnov, P. Paalasmaa, M. Uusisaari, J. Voipio, and K. Kaila
Pharmacological Isolation of the Synaptic and Nonsynaptic Components of the GABA-Mediated Biphasic Response in Rat CA1 Hippocampal Pyramidal Cells
J. Neurosci.,
November 1, 1999;
19(21):
9252 - 9260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bracci, M. Vreugdenhil, S. P. Hack, and J. G. R. Jefferys
On the Synchronizing Mechanisms of Tetanically Induced Hippocampal Oscillations
J. Neurosci.,
September 15, 1999;
19(18):
8104 - 8113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Haenschel, T. Baldeweg, R. J. Croft, M. Whittington, and J. Gruzelier
Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models
PNAS,
June 20, 2000;
97(13):
7645 - 7650.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
