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The Journal of Neuroscience, July 1, 2000, 20(13):5153-5162
Corticothalamic Inputs Control the Pattern of Activity Generated
in Thalamocortical Networks
Hal
Blumenfeld1, 2 and
David A.
McCormick1
1 Section of Neurobiology and 2 Department
of Neurology, Yale University School of Medicine, New Haven,
Connecticut 06520
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ABSTRACT |
Absence seizures (3-4 Hz) and sleep spindles (6-14 Hz) occur
mostly during slow-wave sleep and have been hypothesized to involve the
same corticothalamic network. However, the mechanism by which this
network transforms from one form of activity to the other is not well
understood. Here we examine this question using ferret lateral
geniculate nucleus slices and stimulation of the corticothalamic tract.
A feedback circuit, meant to mimic the cortical influence in
vivo, was arranged such that thalamic burst firing resulted in
stimulation of the corticothalamic tract. Stimuli were either single
shocks to mimic normal action potential firing by cortical neurons or
high-frequency bursts (six shocks at 200 Hz) to simulate increased
cortical firing, such as during seizures. With one corticothalamic stimulus per thalamic burst, 6-10 Hz oscillations resembling spindle waves were generated. However, if the stimulation was a burst, the
network immediately transformed into a 3-4 Hz paroxysmal oscillation. This transition was associated with a strong increase in the burst firing of GABAergic perigeniculate neurons. In addition,
thalamocortical neurons showed a transition from fast (100-150 msec)
IPSPs to slow (~300 msec) IPSPs. The GABAB
receptor antagonist CGP 35348 blocked the slow IPSPs and converted the
3-4 Hz paroxysmal oscillations back to 6-10 Hz spindle waves.
Conversely, the GABAA receptor antagonist picrotoxin
blocked spindle frequency oscillations resulting in 3-4 Hz
oscillations with either single or burst stimuli. We suggest that
differential activation of thalamic GABAA and
GABAB receptors in response to varying corticothalamic
input patterns may be critical in setting the oscillation frequency of
thalamocortical network interactions.
Key words:
GABA; corticothalamic; thalamocortical; absence seizures; petit mal; sleep spindles; epilepsy; sleep; networks
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INTRODUCTION |
Cortical and thalamic networks
interact to generate a variety of normal and abnormal rhythmic states.
These states include spindle waves and absence seizures. Spindle waves
are characterized by 1-4 sec periods of 6-14 Hz oscillation during
normal sleep (Steriade et al., 1993 ). Absence seizures occur most
commonly in young children as staring spells lasting 5-10 sec,
accompanied by a massive 3-4 Hz rhythmic discharge in the EEG
(Niedermeyer, 1990). Sleep spindles and absence seizures may be related
phenomena, as evidenced by their occurrence in the same corticothalamic
network and, most commonly, during the same stages of sleep (Kellaway, 1985; Niedermeyer, 1993). How does the same corticothalamic network that generates 6-14 Hz spindle waves switch to 3-4 Hz spike-wave activity as seen in absence seizures?
Evidence from in vivo animal models suggests that network
interactions involving both cortex and thalamus are important for this
transition (Avoli et al., 1983, 1990; Danober et al., 1998). The
transition to spike-wave seizures is accompanied by a large increase in
firing of cortical neurons during the spike component in comparison
with the activity associated with spindle waves (Kostopoulos et al.,
1981; Avoli and Kostopoulos, 1982; McLachlan et al., 1984; see also
Steriade and Contreras, 1995; Kandel and Buzsaki, 1997; Steriade et
al., 1998). Furthermore, in the feline generalized penicillin epilepsy
model, increased cortical excitability by application of the weak
GABAA antagonist penicillin to the cortex without
application to the thalamus is sufficient to cause a transition to
spike-wave seizures (Avoli and Gloor, 1982), and computational models
of spike-wave generation suggest that cortical disinhibition may result
in low-frequency thalamocortical oscillations (Destexhe, 1998; Destexhe
et al., 1999). How does enhanced cortical firing influence the thalamus
to transform the network to 3-4 Hz paroxysmal activity?
In previous work, the cellular elements of thalamic networks involved
in both sleep spindles and slow 3-4 Hz oscillations have been studied
in detail (Steriade et al., 1993, 1997; McCormick and Bal, 1997).
Spindle waves are generated as a reciprocal interaction between
excitatory thalamocortical cells and inhibitory GABAergic thalamic
reticular or perigeniculate (PGN) cells and depend on fast (100-150
msec) GABAA receptor-mediated IPSPs in
thalamocortical cells to set the network oscillation frequency at 6-14
Hz. Spontaneous 3-4 Hz activity, resembling in some respects that seen
with absence seizures, can be generated in the isolated lateral
geniculate nucleus (LGN) thalamic slice by the block of
GABAA receptors, apparently because of the
generation of large sustained bursts of action potentials in the
GABAergic PGN cells. Dual intracellular recordings from PGN cells
synaptically coupled to thalamocortical cells showed that strong burst
firing in PGN cells can activate slow (~300 msec)
GABAB receptor-mediated IPSPs in thalamocortical cells, setting the network oscillation frequency to 3-4 Hz. Brief bursts of action potentials in PGN cells, on the other hand, primarily activate fast (100-150 msec) GABAA
receptor-mediated IPSPs only and result in the generation of spindle
waves (Kim et al., 1997).
We hypothesize that increased cortical firing may cause increased
firing of GABAergic PGN cells leading to enhanced
GABAB receptor activation in thalamocortical
cells, ultimately triggering a transformation from spindle waves to
3-4 Hz spike-wave seizures, and we have tested this hypothesis using
feedback electrical stimulation of the corticothalamic tract in
geniculate slices.
Parts of this paper have been published previously in abstract form
(Blumenfeld and McCormick, 1999).
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MATERIALS AND METHODS |
Recording and stimulating configuration. Slices of
the ferret dorsal LGN (LGNd) preserve the circuitry needed to generate both spontaneous 6-10 Hz spindle waves and 3-4 Hz slow oscillations (Bal et al., 1995a,b; Kim et al., 1997; McCormick and Bal, 1997). The
influence of corticothalamic input patterns on this network was
investigated using the configuration shown in Figure
1. Intracellular recordings were
performed either from the GABAergic PGN cells or from thalamocortical
cells in the A or A1 laminae. Extracellular multiunit recordings were
obtained immediately adjacent to the thalamocortical cell intracellular
electrode (when one was present) and bandpass filtered between ~300
and 10,000 Hz. The thalamic multiunit activity, representing thalamic
output, was fed into an "artificial cortex" circuit interposed
between thalamic output and input (Fig. 1a). The artificial
cortex consisted of a comparator and a stimulator. When thalamic
extracellular multiunit activity exceeded the threshold of the
comparator, a trigger pulse was passed to the stimulator. The
stimulator then delivered electrical stimuli to the optic radiation,
which contains the corticothalamic fibers, after a short adjustable
delay (0-50 msec), in the range of fast thalamocortical conduction
latencies (Swadlow and Weyand, 1987; Nowak and Bullier, 1997; Timofeev
et al., 1998). The extracellular stimulating electrode was placed in
the optic radiation ~1-2 mm away from the PGN (Fig. 1b).
The stimulator (Master-8; A.M.P.I., Jerusalem, Israel) was set
either to deliver a single 0.1 msec pulse (30-200 µA) to simulate a
low or normal level of cortical firing or to deliver a brief 200 Hz
train of six stimuli, which was meant to simulate a burst of activity
in cortical networks of the kind seen during seizure activity (Fisher
and Prince, 1977; van Brederode and Snyder, 1992). Because the duration
of thalamic bursts was up to ~80 msec, the stimulator was set so that
it would remain refractory for a period of 80 msec after generating a
pulse (or train) to minimize double triggering of the stimulator during a single thalamic burst. This resulted in a maximal allowable spontaneous oscillation frequency of 1000/(80) = 12.5 Hz. During setup, the position of the stimulating electrode, the stimulus strength, and the threshold level of the artificial cortex were adjusted until spontaneous 3-4 Hz oscillations were obtained with 200 Hz trains of six stimuli. Although single spikes could trigger the
stimulator, stimulation was typically triggered only by bursts of
action potentials, because most neurons in the LGNd slice are silent in between the generation of spindle waves and the probability of cells that generate the largest action potentials (e.g., the few
cells close to the electrode) spontaneously discharging in between
spindle waves is low (Bal et al., 1995a,b). After the stimulation
parameters were achieved that were reliably activated by burst firing
in the multiple unit recording and generated strong feedback to the
local thalamic circuit, electrode position, stimulus strength, and
threshold level were kept fixed for the remainder of the experiment.
Although the extracellular stimulating electrode was placed in the
optic radiation, antidromic spikes in thalamocortical cells were rarely
seen, indicating that the excitation of PGN neurons resulted primarily
from activation of corticothalamic fibers. When antidromic spikes were
observed, the stimulating electrode was repositioned, and the stimulus
intensity was reduced until antidromic spikes were eliminated.
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Figure 1.
Artificial cortex circuit. a, The
artificial cortex consisted of a threshold comparator and a stimulator.
The threshold of the comparator was adjusted to be triggered by
multiunit activity in the A laminae of the LGNd. The threshold was
adjusted such that this stimulation unit was usually only activated by
bursts of activity in the LGNd. After being triggered, the stimulator
remained refractory for 80 msec. The stimulator was set to deliver
either single stimuli (0.1 msec; 30-200 µA) or brief 200 Hz bursts
of six stimuli to the optic radiation. b, A drawing of
the placement of recording and stimulating electrodes is shown.
c, d, Intracellular recordings were obtained from
thalamocortical cells (c) or from GABAergic PGN
cells (d). Recordings shown are with the
stimulator set to deliver six corticothalamic stimuli per thalamic
burst, producing sustained PGN cell (GABAergic) firing, slow
GABAB-mediated thalamocortical cell IPSPs, and large
rebound bursts in thalamocortical cells, resulting in spontaneous 3-4
Hz oscillations.
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Slice preparation. Male or female 2- to 3-month-old ferrets
were deeply anesthetized with sodium pentobarbital (30 mg/kg, i.p.) and
killed by decapitation. The brain was rapidly removed and placed into a
chilled aerated solution in which NaCl was replaced with sucrose while
an osmolarity of 307 mOsm was maintained (Aghajanian and Rasmussen,
1989). This sucrose-substituted solution was used during the remainder
of the slice preparation procedure to improve tissue viability. The
hemispheres were separated with a midline incision. A vibratome (DSK
microslicer; Ted Pella, Irvine, CA) was used to obtain sagittal slices
(400 µm thick) of the lateral geniculate nucleus. Slices were then
transferred to an interface-style recording chamber (Fine Science
Tools, North Vancouver, British Columbia, Canada) and allowed at least
2 hr to recover before recordings. The perfusion medium was an
artificial CSF (ACSF) containing (in mM): NaCl 126, KCl 2.5, MgSO4 1.2 or 2.0, NaH2PO4 1.25, CaCl2 2, NaHCO3 26, and
dextrose 10, aerated with 95% O2 and 5%
CO2 to a final pH of 7.4. For the first 20 min
that the slices were in the recording chamber, the medium contained an equal mixture of 2.0 mM MgSO4 ACSF
and the sucrose-substituted solution. For the next 60 min, the slices
were perfused with 2.0 mM MgSO4 ACSF.
The solution was then changed to ACSF with 1.2 mM
MgSO4 for the remainder of the experiment. Bath
temperature was maintained at 34-35°C. Only slices that generated
spontaneous spindle-wave oscillations were used for these experiments.
Microelectrodes. Intracellular recording electrodes were
pulled using medium-walled glass (1BF 100; World Precision Instruments, Sarasota, FL) on a Sutter Instruments P-80 micropipette puller (Novato,
CA). Microelectrodes were filled with 1.2 M K-acetate and
beveled to a final resistance of 60-120 M . Extracellular multiunit
recordings were obtained with low-resistance (<1 M) tungsten
microelectrodes (Fredrick Haer Corporation, Bowdoinham, ME). Electrical
stimulation (30-200 µA; 0.1 msec duration) was performed using a
constant-current generator (World Precision Instruments) and
passed through a concentric bipolar stimulating electrode (Fredrick
Haer Corporation).
Drug application. CGP 35348 (Novartis, Basel, Switzerland)
or picrotoxin (Sigma, St. Louis, MO) was added either by bath perfusion (200 µM CGP 35348 or 100 µM picrotoxin) or
puffer pipette (2 mM CGP 35348 or 1 mM
picrotoxin in the pipette) in which a brief pulse of pressurized
N2 (10-250 msec; 200-350 kPa) was applied to
the back of a broken microelectrode (1-4 µm tip diameter) to extrude
an ~1-20 pl droplet of solution. In all experiments in which drugs
were applied, baseline control data were first obtained (see
Fig. 7b). Oscillation measurements were then repeated 30 min
after changing the bath perfusion or immediately after drug application
by puffer pipette.
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RESULTS |
Corticothalamic input pattern determines thalamocortical
oscillation frequency
Slices of the ferret dorsal LGN preserve the circuitry needed to
generate both 6-10 Hz spindle waves and 3-4 Hz slow oscillations (Bal
et al., 1995a,b; Kim et al., 1997; McCormick and Bal, 1997). To test
the role of corticothalamic inputs in generating these two distinct
rhythms, feedback stimulation of corticothalamic fibers was used (Fig.
1) with either single 0.1 msec shocks to mimic normal cortical firing
or brief bursts of six shocks at 200 Hz to mimic abnormally enhanced
cortical excitability (Fisher and Prince, 1977; van Brederode and
Snyder, 1992).
Spontaneous spindle waves occurred in LGN thalamic slices with an
intrinsic frequency of 6-10 Hz as described previously (Bal et al.,
1995a,b). Intracellular recordings from thalamocortical cells during
these events (Fig. 2a,b)
exhibited rhythmic alternating IPSPs and low-threshold calcium spikes
crowned by occasional action potentials. IPSPs had a mean duration of
167 ± 4.6 msec (± SEM; n = 16),
resulting in a mean oscillation frequency of 6.05 ± 0.15 Hz
(n = 16). The total duration of each spindle wave was
3-10 sec (4.49 ± 0.46 sec; n = 16), and these
events spontaneously recurred every 20-30 sec, with a relatively
quiescent period intervening between each spindle. When the artificial
cortex was added to the circuit and set to deliver one stimulus
each time it was triggered by thalamocortical activity, spontaneous
oscillations occurred as well, often initiated by the onset of a
spindle wave (Fig. 2c). These resembled spindle waves in
oscillation frequency (6.4 ± 0.15 Hz; n = 16) and
in IPSP shape and duration (157 ± 4.2 msec; n = 16) (Fig. 2d). Network oscillations generated with
single-shock stimuli were slightly longer in total duration (8.85 ± 1.42 sec; n = 16; p < 0.01, two-tailed t test) and were followed by a small slow
afterdepolarization, as seen in normal spindles (Bal and McCormick,
1996). When the electrical stimulator was instead set to deliver a
burst of six stimuli in response to thalamocortical activity, there was
a marked transformation of the network activity (Fig. 2e) to
a 3-4 Hz (3.32 ± 0.12 Hz; n = 16;
p < 0.0001, two-tailed t test) event. The
mean IPSP duration in thalamocortical cells increased to 307 ± 10 msec (± SEM; n = 16; p < 0.0001, two-tailed t test), and stronger rebound bursts of
three or more action potentials occurred in these cells with each cycle
(Fig. 2f). These changes were observed in
extracellular recordings from 49 ferret LGN slices and in intracellular
recordings from 34 thalamocortical cells. Quantitative analysis was
performed on 16 of these experiments in which drugs were applied (see
Fig. 7b below).
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Figure 2.
Single corticothalamic stimuli elicit 6-10 Hz
spindle waves, whereas high-frequency bursts of six stimuli elicit 3-4
Hz oscillations. a, A recording of a spontaneous spindle
wave with the LGN extracellular electrode (top
trace) demonstrates waxing and waning bursts of
multiunit activity at 6-10 Hz. An intracellular recording from a
thalamocortical cell (bottom trace)
demonstrates rhythmic fast (100-150 msec) IPSPs with rebound
Ca2+ spikes that occasionally generate action
potentials. Action potentials are clipped at this magnification.
b, An expanded trace of the intracellular
recording in a from the portion indicated by the
thick horizontal line is
shown. c, With the stimulation of the corticothalamic
tract once per activation, the network generated spontaneous
oscillations that resemble spindle waves in both frequency and IPSP
shape, although they were typically longer in duration. Extracellular
recordings (top trace) demonstrate both
multiunit activity and a larger field potential evoked by the stimulus.
Stimulus pulses are represented by tick
marks (or ovals; see Fig. 3)
below the traces in this and all other
figures. Stimulus artifacts were removed manually from this and
all other recordings illustrated. d, An expanded
trace of the intracellular recording in c
(bottom trace) from the portion indicated
by the thick horizontal
line is shown. e, With the stimulator set
to deliver 200 Hz bursts of six stimuli for each thalamic burst, the
network transforms to 3-4 Hz activity, with slow (~300 msec) IPSPs
and increased rebound burst firing. The discharge of various single
neurons intracellularly recorded (bottom
trace) occurred at different times in relationship to
the multiunit extracellular burst (top
trace). Thus, the thalamocortical cell recorded
here fired relatively early in the burst, whereas the thalamocortical
cell shown below (see Fig. 5) fired later in the burst.
f, An expanded trace of the intracellular
recording in e from the portion indicated by the
thick horizontal line is
shown.
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Oscillations terminated when a burst occurred in the thalamic slice
that was below the threshold of the comparator (Figs. 1a,
2c,e). Mean oscillation frequency was somewhat higher at the beginning of each event (7.18 ± 0.22 Hz, one shock; 3.65 ± 0.13 Hz, six shocks) than at the end (5.82 ± 0.18 Hz, one shock;
3.05 ± 0.12 Hz, six shocks; n = 16;
p < 0.0001 and < 0.005 for one and six shocks,
respectively, two-tailed t test).
Lengthening of the IPSPs from short to long duration is mediated by
an increased duration of spike bursts in GABAergic neurons
As discussed above, thalamocortical cell IPSPs were of
significantly shorter duration in response to single versus burst
stimulation, presumably because of differences in GABAergic cell
activity (Kim et al., 1997). To test this hypothesis, we performed
intracellular recordings from the GABAergic PGN cells during the
different stimulation protocols. During spontaneous spindle waves, PGN
cells exhibited rhythmic EPSPs and low-threshold calcium spikes
at 6-10 Hz with superimposed burst firing (Fig.
3a,d) of approximately three
to five action potentials per cycle, as reported previously (Bal et
al., 1995a,b). When the corticothalamic tract was stimulated once per
thalamic burst, the oscillation frequency, PSP pattern, and burst
firing were similar to that seen during spindles (Fig. 3b,e). With six stimuli per burst, the oscillation frequency
immediately slowed to 3-4 Hz as discussed above (Fig. 3c).
In addition, there was a marked increase in PGN cell burst firing of
12-15 action potentials per cycle (Fig. 3f;
n = 8). These findings suggest that normal brief
corticothalamic firing causes brief action potential bursts in PGN
cells resulting in fast IPSPs in thalamocortical cells, presumably via
GABAA receptors, whereas more intense
corticothalamic firing causes sustained action potential bursts in PGN
cells resulting in slow IPSPs in thalamocortical cells, possibly
mediated by GABAB receptors.
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Figure 3.
Single corticothalamic stimuli elicit brief PGN
cell (GABAergic) bursts, whereas high-frequency bursts of six stimuli
elicit sustained PGN cell burst firing. a, Spontaneous
spindle wave (no stimulation). The LGNd extracellular recording
(top trace) shows rhythmic 6-10 Hz burst
firing. The PGN (GABAergic) cell intracellular recording
(bottom trace) shows rhythmic EPSPs and
Ca2+ spikes with superimposed action potential burst
firing. b, Stimulator set to deliver one stimulus per
thalamic burst. With this stimulation, spontaneous 6-10 Hz
oscillations resembling spindle waves in both oscillation frequency and
PGN cell burst firing are generated. c, Stimulator set
to deliver a high-frequency (200 Hz) burst of six stimuli
to the optic radiation each time it is triggered. Oscillation frequency
is slower, at 3-4 Hz, with markedly increased burst firing of PGN
cells. d-f, Expanded traces of the
intracellular recordings in a-c from the portions
indicated by the thick horizontal
lines. Note the burst firing of 3-5 action potentials
in PGN cells during spontaneous spindle waves (d)
or with single corticothalamic stimuli (e),
whereas six corticothalamic stimuli elicit greatly increased bursts of
12-15 action potentials (f).
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GABAB receptor antagonist blocks both slow IPSPs and
slow 3-4 Hz oscillations
To investigate the role of GABAB receptors
in the transition from 6-10 to 3-4 Hz spontaneous oscillations, we
used the GABAB antagonist CGP 35348. Under normal
conditions, one corticothalamic shock per cycle produced 6-10 Hz
oscillations with fast IPSPs recorded from thalamocortical cells (see
Figs. 4a, 5a, 7b), whereas six stimuli
per cycle caused a transition to 3-4 Hz oscillations with slow IPSPs
(see Figs. 4b, 5b, 7b). However,
application of the GABAB antagonist CGP 35348 (200 µM bath application or 2 mM in the puffer pipette) blocked this transition
(see Figs. 4c,d, 5d-f, 7b). Thus, in
the presence of CGP 35348, both one and six shocks per cycle resulted
in a similar oscillation frequency of 6-10 Hz [see Fig.
7b; 7.17 ± 0.23 Hz (n = 10), one
shock; 6.72 ± 0.28 Hz (n = 11), six shocks;
p = 0.23, two-tailed t test]. In CGP 35348, the oscillation frequency with six shocks was significantly faster than
that of the control (see Fig. 7b; p < 0.0001), whereas spindle waves and oscillations with one shock were
only slightly faster than that of the control (see Fig. 7b;
p < 0.01 for both). Washout of CGP 35348 led to
reversal of these effects in seven of seven experiments.
In CGP 35348 the durations of spontaneous spindle waves (3.11 ± 0.32 sec; n = 11) and of oscillations with one shock
per cycle (7.10 ± 1.78 sec; n = 10) were similar
to control conditions (see above). However, as shown in the three
examples in Figure 4d, six
shocks per cycle in the presence of CGP 35348 produced only short
periods of oscillation (mean duration = 1.44 ± 0.55 sec; n = 10). These were significantly shorter than the more
sustained oscillations seen under control conditions with six shocks
(mean duration = 6.00 ± 0.67 sec; n = 16;
p < 0.0001, two-tailed t test). The
membrane potential during six shocks per cycle had a more sustained
hyperpolarization in control conditions than in the presence of CGP
35348 (Fig. 4e; n = 8 intracellular
recordings), possibly leading to early termination of the oscillations
in the presence of this GABAB receptor
antagonist.
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Figure 4.
GABAB receptor antagonist
CGP 35348 blocks stimulus-induced 3-4 Hz oscillations. a,
b, Extracellular (top traces) and
intracellular (bottom traces) recordings
of thalamocortical cells in control solution are shown.
a, One corticothalamic shock per thalamic burst elicits
spontaneous oscillations that resemble spindle waves, with fast
(100-150 msec) IPSPs and an intrinsic frequency of 6-10 Hz.
b, At six shocks per thalamic burst, slow (~300 msec)
IPSPs occur with an oscillation frequency of 3-4 Hz. c,
Local application of CGP 35348 (2 mM in the puffer pipette)
has no effect on the spindle wave-like (6-10 Hz) oscillations seen
with one shock per thalamic burst. d, However, six
shocks per burst now produce spindle wave-like (6-10 Hz) oscillations
as well and no longer produce 3-4 Hz rhythms. In addition,
oscillations are of shorter duration (three examples shown).
Spontaneous spindle waves (like those in Fig. 2a) also
continue to occur in the presence of CGP 35348 (data not shown). Action
potentials are clipped at this magnification. e, An
overlay of recordings with six shocks from control
(b) and CGP 35348 (d,
left trace) reveals more sustained
hyperpolarization under control conditions.
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The postsynaptic potential produced by single stimuli consisted
primarily of a short-duration IPSP (158 ± 4.2 msec;
n = 16) (Fig.
5a), presumably mediated by
GABAA receptors. The postsynaptic potential
produced by six stimuli was more complicated (Fig. 5b) and
can best be appreciated when overlaid on the response to a single shock
(Fig. 5c,f). The response to six stimuli included an
early event consisting of both EPSPs and IPSPs followed by a slow IPSP
lasting ~300 msec (307 ± 10.9 msec; n = 16).
When GABAB receptors were blocked by CGP 35348, one stimulus per cycle still produced fast (141 ± 4.7 msec;
n = 10) IPSPs (Fig. 5d). With six stimuli
per cycle in CGP 35348 (Fig. 5e), the slow IPSP was blocked,
and IPSPs had a mean duration of 152 ± 6.5 msec
(n = 11), similar to that seen with single shocks or
during spindle waves. Comparing the response to six shocks per cycle
before and after the application of CGP 35348 revealed that the early
fast IPSP-EPSP complex was preserved despite blockade of the slow IPSP (Fig. 5, compare b, e). These findings strongly
suggest that bursts of corticothalamic input cause slow IPSPs and 3-4
Hz oscillations via activation of GABAB
receptors.
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Figure 5.
GABAB receptor antagonist CGP 35348 blocks thalamocortical cell slow IPSPs. a-c,
Intracellular recordings from a thalamocortical cell in control
solution are shown. Traces from Figure 4,
a and b, are enlarged (action potentials
are clipped). a, One corticothalamic shock per thalamic
burst produces fast (100-150 msec) IPSPs and brief rebound bursts in
thalamocortical cells. b, Six shocks per burst produce
slow (~300 msec) IPSPs and stronger rebound burst firing.
c, An overlay of the traces reveals that
with six shocks there is an early fast IPSP-EPSP complex followed by a
slow IPSP. Arrows with the numbers 1 or 6 indicate the number of shocks per burst. d-f,
Recordings from a thalamocortical cell after local application of CGP
35348 (2 mM in the puffer pipette) are shown.
Traces from Figure 4, c and
d, are enlarged. d, One shock per burst
still produces fast (100-150 msec) IPSPs. e, However,
six shocks per burst now also produce fast (100-150 msec) spindle
wave-like IPSPs. f, An overlay of the
traces reveals that the slow IPSP is blocked, suggesting
that it is mediated by GABAB receptors. However, six shocks
still produce an early fast IPSP-EPSP complex.
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GABAA receptor antagonist blocks fast IPSPs and fast
6-10 Hz oscillations
What is the role of GABAA receptors in
preventing 3-4 Hz oscillations in thalamic slices? Previously, we have
reported that the block of GABAA receptors in
geniculate slices results in the generation of 3-4 Hz spontaneous
paroxysmal network discharges, resulting from strong bursts of activity
in PGN GABAergic neurons (Bal et al., 1995a,b; Kim et al., 1997).
Similarly, we found here that addition of the
GABAA receptor antagonist picrotoxin (100 µM bath perfusion or 1 mM in the puffer
pipette) resulted in ~3 Hz oscillations whether the corticothalamic
fibers were stimulated once or six times per thalamic burst (Fig.
6a,b). Fast IPSPs were blocked, and instead large slow ~300 msec IPSPs were seen, with increased rebound burst firing of thalamocortical cells regardless of
the corticothalamic stimulus (Fig. 6c,d). Oscillation
frequencies with one (2.95 ± 0.15 Hz) or six (2.69 ± 0.15 Hz) shocks per cycle were similar (n = 6;
p = 0.24, two-tailed t test), but the
oscillation frequency with one shock per cycle was significantly slower
than that of control (Fig. 7b;
p < 0.0001). Durations of individual oscillations in
the presence of picrotoxin [6.67 ± 0.68 sec (n = 6), one shock per cycle; 8.21 ± 2.25 sec (n = 6),
six shocks per cycle] were not significantly different from control.
These findings suggest that fast thalamocortical IPSPs in response to single corticothalamic stimuli, like those during spindle waves (Bal et
al., 1995a,b; Kim et al., 1997; McCormick and Bal, 1997), are mediated
by GABAA receptors. In addition,
GABAA receptor-mediated PGN-to-PGN cell
inhibition (Huguenard and Prince, 1994; Sanchez-Vives and McCormick,
1997; Sanchez-Vives et al., 1997) may normally reduce GABAergic input
to thalamocortical cells. Thus, blockade of GABAA
receptors results in increased GABAergic input to thalamocortical cells, producing large GABAB-mediated slow IPSPs
not seen with single stimuli under control conditions.
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Figure 6.
The GABAA receptor antagonist
picrotoxin blocks 6-10 Hz oscillations and fast IPSPs. a,
b, Thalamocortical cell intracellular (bottom
traces) and extracellular (top
traces) recordings in the presence of picrotoxin (100 µM in bath perfusion). Either one
(a) or six (b)
corticothalamic shocks per thalamic burst elicit slow (~300 msec)
IPSPs with large rebound bursts (action potentials are clipped at this
magnification) and spontaneous 3-4 Hz oscillations. Under control
conditions, this thalamic slice and thalamocortical cell exhibited
6-10 Hz oscillations with one shock per burst and 3-4 Hz oscillations
with six shocks per burst (data not shown). c, d,
Expanded traces from segments indicated by the
thick horizontal lines in a
(c) and b
(d).
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Figure 7.
Summary of effects of corticothalamic burst
intensity and GABAA and GABAB antagonists.
a, One corticothalamic stimulus per thalamic burst
produces spontaneous 6-7 Hz spindle wave-like oscillations
(leftmost bar in
histogram). As the number of stimuli in the 200 Hz burst
is increased, the oscillation frequency gradually slows until it
reaches 3-4 Hz at six stimuli per burst. Further increases in the
number of stimuli do not produce large changes in oscillation
frequency, possibly because GABAB receptors are maximally
activated. Data are from the cell illustrated in Figures 4 and 5. The
numbers of interstimulus intervals averaged to calculate oscillation
frequencies for 1 through 10 stimuli were 54, 19, 21, 18, 26, 47, 22, 13, 16, and 14, respectively. b, Effects of the
GABAB antagonist CGP 35348 and the GABAA
antagonist picrotoxin on network oscillation frequency are shown. In
control conditions, the oscillation frequency is 6-7 Hz in spontaneous
spindle waves (no stimuli) and with one stimulus per cycle, whereas it
is ~3 Hz when bursts of six stimuli are used. In the presence of CGP
35348, the oscillation frequency remains at 6-7 Hz whether one or six
stimuli are given. In picrotoxin, the oscillation frequency is ~3 Hz
regardless of whether one or six stimuli are given. Group frequency
data are shown from 13 intracellular and 3 extracellular recordings in
which one or both drugs were applied. Mean and SEM values for all
frequencies are listed in Results. The following frequency changes were
significant at the p < 0.0001 level (two-tailed
t test): control one stimulus versus control six
stimuli, control six stimuli versus CGP 35348 six stimuli, and control
one stimulus versus picrotoxin one stimulus.
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Effects of varying corticothalamic stimulation parameters
The parameters of the corticothalamic stimulation were varied to
determine which were critical to the transformation of 6-10 Hz
spindle-like oscillations into the 3-4 Hz "paroxysmal" events. We
varied the number of shocks in each burst (n = 6), the
intensity of each shock (n = 7), the frequency of
stimulation within the burst (n = 5), and the delay
between the detected multiple unit activity in the LGNd and the
stimulation of the optic radiation (n = 4). We found
that the most important parameters were stimulus intensity and the
number of stimuli in the burst. As the number of stimuli in the 200 Hz
corticothalamic burst was increased from one to six, the spontaneous
oscillation frequency gradually decreased from 6-10 to 3-4 Hz (Fig.
7a). Further increases in the number of stimuli did not
cause marked changes in the frequency, possibly because thalamocortical
cell GABAB receptors were maximally activated. A
similar relationship was found as the stimulus intensity was increased
over the range of 30-200 µA, as long as at least two stimuli were
present in the 200 Hz burst. Thus, low-intensity stimuli resulted in
6-10 Hz oscillations even if six stimuli were used, whereas higher
intensity stimuli produced 3-4 Hz oscillations. With single stimuli,
slow oscillations could not be produced unless very high (>1 mA)
stimulus intensities were used.
Other parameters did not have dramatic effects on the oscillation
frequency. The transformation to 3-4 Hz oscillations with six stimuli
could be obtained as long as the intraburst frequency was between 40 and 300 Hz. With intraburst frequencies below 40 Hz, the burst of six
stimuli lasted for >125 msec, resulting in repeated and continuous
feedback stimulation of the optic radiation at a frequency of ~10 Hz.
As the intraburst frequency was increased above 300 Hz, the efficiency
of corticothalamic activation decreased so that oscillations at 6-10
Hz were evoked, resembling those seen with single stimuli. The delay in
the artificial cortex circuit was varied between 0 and 50 msec but was
set at 5 msec for most experiments. This is within the range of the
fastest-conducting axons between the cortex and thalamus (Swadlow and
Weyand, 1987; Nowak and Bullier, 1997; Timofeev et al., 1998). Changing
the delay in the artificial cortex circuit in the range of 0-50 msec had no effect on the oscillations except to add the time of the delay
itself to the oscillation cycle.
| |
DISCUSSION |
Corticothalamic interactions during sleep spindles and
epileptiform activity have been studied previously in a number of
systems. In vivo studies in cats and rodents have shown a
large increase in rhythmic firing of both cortical and thalamic neurons
during spike-wave seizures compared with spindle waves (Fisher and
Prince, 1977; Kostopoulos et al., 1981; Avoli and Kostopoulos, 1982,
1983, 1990; McLachlan et al., 1984; Steriade and Contreras, 1995;
Steriade et al., 1997, 1998; Kandel and Buzsaki, 1997; Danober et al., 1998). Although some studies have suggested that either the cortex (Steriade and Contreras, 1998) or thalamus (von Krosigk et al., 1993;
Castro-Alamancos, 1999) alone can generate 3-4 Hz seizure-like activity, most evidence supports the importance of both structures interacting via reciprocal network connections in generating this abnormal rhythm (Avoli and Kostopoulos, 1982, 1990; Gloor et al., 1990;
Danober et al., 1998). Topical application of the
GABAA antagonists penicillin or bicuculline to
the cortex, but not the thalamus, is sufficient to convert the
corticothalamic network from spindle waves to 3-4 Hz spike-wave
seizures (Avoli and Gloor, 1982; Avoli and Kostopoulos, 1982; Steriade
and Contreras, 1998). This suggests that abnormally increased cortical
firing is capable of switching the network from normal spindle waves to
spike-wave seizures. How could increased firing of cortical neurons
produce this transition?
Corticothalamic fibers form excitatory synapses in the thalamus on both
thalamocortical neurons and GABAergic reticular thalamic cells (PGN
cells in the LGN region), as well as local interneurons. The discharge
of brief bursts of action potentials in PGN neurons produces fast
(100-150 msec) IPSPs mediated by GABAA
receptors, whereas the firing of sustained bursts in PGN cells elicits,
in addition to GABAA IPSPs, slow (~300 msec)
GABAB receptor-mediated IPSPs in thalamocortical
cells (Kim et al., 1997). We have shown here that increased firing in
the corticothalamic pathway may be able to transform PGN cell discharge
from brief to sustained bursts of action potentials (see also
Blumenfeld and McCormick, 1999; Debay et al., 1999), as is seen in
these cells in the transition from spindles to spike-wave seizures
(Neckelmann et al., 1998; Timofeev et al., 1998). This transition is
accompanied by a change in thalamocortical cell IPSPs from fast to slow
and in spontaneous oscillations from spindle waves to 3-4 Hz
seizure-like events. It is possible, or even likely, that our
electrical stimulation of the optic radiation also antidromically
activated thalamocortical cells and thus activated PGN cells via
collaterals of these axons. However, antidromic action potentials were
only rarely observed with intracellular recordings of thalamocortical
cells, suggesting that this was not the dominant mechanism by which PGN
cells were activated by this stimulation. Interestingly, previous
in vivo studies have demonstrated antidromic activation of
thalamocortical axons during seizure generation (Noebels and Prince,
1978; Pinault and Pumain, 1989), suggesting that this mechanism may
contribute to these pathological events.
What effects does increased corticothalamic firing have on the
thalamocortical network, and how does this cause a transformation to
slow 3-4 Hz paroxysmal activity? There are several possible mechanisms
that may contribute to this transition. As shown here, increased
corticothalamic firing may produce increased burst firing of GABAergic
PGN neurons resulting in slow ~300 msec
GABAB-mediated IPSPs in thalamocortical cells.
These slow IPSPs are particularly effective in removing inactivation of
the low-threshold Ca2+ current and
therefore in generating large, delayed rebound bursts of action
potentials that initiate the next cycle of the oscillation. Thus,
activation of ~300 msec GABAB-mediated IPSPs
may be critical to setting the oscillation frequency of spike-wave
seizure. However, in addition to the
GABAB-mediated slow IPSP in thalamocortical cells, burst firing in corticothalamic inputs may also activate several
other synaptic changes in the thalamocortical network. Previous work
(Kim and McCormick, 1998; von Krosigk et al., 1999) has shown a
decrement in GABAA-mediated fast IPSPs with
repeated firing of presynaptic GABAergic neurons. This may be caused by postsynaptic GABAA receptor desensitization or
presynaptic GABAB receptor-mediated
autoinhibition (Thompson et al., 1993; Wu and Saggau, 1995). In
addition, repetitive firing in the corticothalamic pathway causes
facilitation of EPSPs in thalamocortical cells (Deschênes and Hu,
1990; von Krosigk et al., 1999). One could postulate that these two
effects of corticothalamic burst firing (decrement of fast IPSPs, and
enhancement of EPSPs) alter the early phase of the thalamocortical cell
response so that a prominent early hyperpolarization is no longer
present, thus preventing early rebound bursts and promoting slow
oscillations (Fig. 5a-c). However, the change in shape of
the early phase of the thalamocortical cell response alone is not
sufficient to produce delayed rebound bursts and 3-4 Hz oscillations
(Fig. 5d-f). Thus, when the slow IPSP was blocked
with the GABAB antagonist CGP 35348, early
rebound bursts returned (Fig. 5e), and a reversion to 6-10
Hz oscillations was seen. These findings suggest that enhanced
activation of GABAB receptors in thalamocortical
cells in response to increased corticothalamic inputs may be critical
to setting the oscillation frequency during spike-wave seizures at 3-4
Hz (Hosford et al., 1992; Castro-Alamancos, 1999).
Why are sustained bursts required in GABAergic PGN cells to activate
GABAB receptors in thalamocortical cells?
Previous work with hippocampal (Sodickson and Bean, 1996), cortical
(Thomson and Destexhe, 1999), and thalamic (Kim et al., 1997; Kim and
McCormick, 1998) neurons has shown that GABAB
receptor-mediated IPSPs activate relatively slowly, possibly because of
the kinetics of G-protein-mediated receptor-channel interactions
(Destexhe and Sejnowski, 1995; Thomson and Destexhe, 1999). In addition
it has been proposed that GABAB receptors may be
located extrasynaptically and could, therefore, require more
presynaptic GABA release for spillover to the
GABAB receptor sites to occur (Mody et al.,
1994). Differential activation of GABAA and
GABAB receptors by different activity patterns
may explain why GABAA agonists such as clonazepam
reduce absence seizures (Huguenard and Prince, 1994; Huguenard, 1999),
whereas agents such as the GABA transaminase inhibitor vigabatrin that
causes a generalized increase in brain GABA levels can exacerbate
absence seizures (Guberman, 1996).
One widely used model of absence seizures is the generation of
spike-wave attacks in rats, particularly in the WAG/Rij or genetic
absence epilepsy rats from Strasbourg strains (Buzsaki et al., 1988;
Coenen et al., 1992; Marescaux et al., 1992; Vergnes and Marescaux,
1992). Although these seizures depend on the interaction of the
thalamus and cerebral cortex and are blocked by lesions of the thalamic
reticular nucleus, the precise role for GABAB receptors is unclear, because the frequency of these spike-wave seizures is in the range of 6-8 Hz (Pinault et al., 1998).
Computational models suggest that GABAB receptors
may facilitate spike-wave seizure activity in rodents by activating a
relatively sustained hyperpolarization of the membrane potential, which
enhances the ability of fast GABAA IPSPs to
generate rebound Ca2+ spikes and action
potentials (Destexhe et al., 1999). In any case, the interaction
of the cerebral cortex and thalamus and, particularly, the activation
of strong GABAergic IPSPs in thalamocortical neurons appear to be
critically important in the generation of several forms of spike-wave seizures.
The recording arrangement used for our present studies has several
advantages not present in other preparations. The artificial cortex
circuit allows a variety of cortical input and output parameters to be
studied. Use of sagittal slices of the ferret LGN preserves the
intrinsic thalamic circuitry needed to generate spontaneous oscillations (Bal et al., 1995a,b). The 3-4 Hz oscillations that we
observed with this circuit resemble those seen in absence seizures (Kellaway, 1985; Engel and Pedley, 1999) in that they were often initiated by a spindle wave and the frequency was slightly higher at
the beginning than at the end of each oscillation.
The mechanism for the slowing of oscillation frequency during the
course of each event remains unknown and warrants further investigation. Interestingly, spontaneous spindle waves had a slightly
shorter duration than did oscillations elicited with one shock per
cycle. The small afterdepolarization seen after spindle waves because
of persistent activation of the hyperpolarization-activated cation
current Ih (Bal and McCormick, 1996) was
also present with one shock per cycle. Thus, one could speculate that
optic radiation stimulation enhances spindle waves, requiring larger
increases in Ih for the spindle waves to
stop. Another phenomenon for which the mechanism is presently unknown
is the shorter duration of oscillations produced by bursts of six
shocks in the presence of CGP 35348 (Fig. 4d,e). Close
examination of the membrane potential traces revealed that after the
block of GABAB receptors the membrane potential
did not hyperpolarize as much as in the control, during the generation
of rhythmic network oscillations. Thus, the activation of
GABAB receptors may facilitate the maintained
hyperpolarization of thalamocortical cells, prolonging the network oscillations.
Our findings provide an important example of the dynamic state of
interactions between the cerebral cortex and thalamus. The generation
of both normal and abnormal patterns of activity depend on the status
of local as well as global network interactions. In the case of
abnormal paroxysmal oscillations, primary deficits at any of a number
of locations may result in a relatively similar pattern of activity.
For example, disinhibition of thalamic reticular neurons from one and
another (von Krosigk et al., 1993; Sanchez-Vives and McCormick, 1997;
Sanchez-Vives et al., 1997; Huntsman et al., 1999), generation of
low-threshold Ca2+ spikes in thalamic
reticular neurons that are larger than usual (Tsakiridou et al., 1995),
overly strong activation of GABAB receptors on
thalamocortical neurons (von Krosigk et al., 1993), or, as supported by
the present study, abnormally strong responses of cortical networks to
thalamic volleys may all lead to the perversion of thalamocortical
networks into the generation of abnormal rhythms. The findings reported
here demonstrate how increased activity in one portion of a network
may, via differential effects on neurotransmitter systems and
appropriate feedback, transform the global activity pattern of the
entire network. Understanding the mechanisms for switching network
activity patterns may be essential for explaining the transitions
occurring during normal states of sleep and arousal, as well as the
generation of seizures, tremors, and possibly a wide variety of other
neurological disorders.
| |
FOOTNOTES |
Received Feb. 28, 2000; revised April 7, 2000; accepted April 13, 2000.
This work was supported by National Institutes of Health Grants NS
02060 to H.B. and NS 26143 to D.A.M. and by a Pfizer postdoctoral fellowship to H.B. CGP 35348 was generously provided by Novartis. We
thank Drs. Joshua Brumberg, Anita Luthi, and Uhnoh Kim for helpful
discussions and comments on this manuscript.
Correspondence should be addressed to Dr. Hal Blumenfeld, Yale
University School of Medicine, Neurobiology, 333 Cedar Street, New
Haven, CT 06520. E-mail: hal.blumenfeld{at}yale.edu.
| |
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ABSTRACT
INTRODUCTION
