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The Journal of Neuroscience, November 1, 1998, 18(21):9002-9009
Mediodorsal Thalamus Plays a Critical Role in the Development of
Limbic Motor Seizures
Robert M.
Cassidy and
Karen
Gale
Interdisciplinary Program in Neuroscience and Department of
Pharmacology, Georgetown University Medical Center, Washington, DC
20007
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ABSTRACT |
Limbic motor seizures in animals, analogous to complex partial
seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD.
This study examined the functional role of MD in focally evoked limbic
motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic
transmissions in MD were evaluated for an influence on seizures evoked
from area tempestas (AT), a discrete epileptogenic site in the rostral
piriform cortex.
A GABAA receptor agonist, Glu receptor antagonists, or a
GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAA
agonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of
2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In
contrast, focal pretreatment of MD with a competitive antagonist of the
NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not
attenuate seizures. The anticonvulsant effects achieved with intra-MD
injections of muscimol and NBQX were site-specific, because no seizure
protection was obtained with injections placed 2 mm ventral or lateral
to MD. Prolonged seizure protection was obtained following GABA
elevation in MD after the application of the GABA transaminase
inhibitor vigabatrin (194 nmol). These results suggest the following:
(1) MD is a critical participant in the generation of seizures elicited
focally from piriform cortex; (2) transmission via AMPA receptors, but
not NMDA receptors, in MD regulates limbic seizure propagation; and (3)
a GABA-mediated system exists within MD, the enhancement of which
protects against focally evoked limbic motor seizures.
Key words:
area tempestas; piriform cortex; bicuculline; GABA; glutamate; vigabatrin
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INTRODUCTION |
Area tempestas (AT) is a
functionally defined, discrete epileptogenic site deep within the
anterior piriform cortex, which has been identified in the rat and
monkey (Piredda and Gale, 1985 ; Gale and Dubach, 1993). In the rat,
unilateral microinjection of picomole amounts of GABA receptor
antagonists or glutamate (Glu) receptor agonists elicits synchronous
bilateral electrographic and motor seizures, characterized by facial
and forelimb clonus with rearing and loss of balance (Piredda and Gale,
1985); this type of seizure, often referred to as "limbic motor
seizure", is analogous to secondarily generalized complex partial
seizures in humans (McNamara et al., 1993). Two neurochemical
substrates within AT are crucial to seizure genesis: inhibitory
GABAergic transmission and excitatory glutamatergic transmission. A
tonic balance between excitatory glutamatergic input and inhibitory GABAergic input exists within AT, and the unilateral disruption of this
balance in favor of excitation triggers seizures. Accordingly, focal
injection of bicuculline, a GABAA receptor antagonist,
removes the endogenous inhibitory control in AT and allows the
endogenous excitatory drive to evoke limbic motor seizures (Piredda and
Gale, 1986a). In the rat, the local blockade of either NMDA or AMPA receptors protects against seizure activity elicited by focal bicuculline, indicating that both subtypes of Glu receptor are necessary for seizure initiation from AT (Piredda and Gale, 1986a; Tortorella et al., 1997).
Studies mapping increases in metabolic activity, as indicated by the
uptake of [14C]2-deoxyglucose (2DG), have found
that seizures evoked from anterior piriform cortex produce a marked
increase in cellular metabolism in a specific set of forebrain regions.
These areas include olfactory bulbs, posterior piriform cortex,
perirhinal cortex, amygdala, entorhinal cortex, and mediodorsal
thalamus (MD) (see Fig. 1) (Gale, 1993; White and Price, 1993).
Similarly, a time course of immunohistochemical localization of heat
shock protein during ictal activity elicited from unilateral injections
of bicuculline into AT demonstrates that this cellular stress marker is
expressed preferentially in the ipsilateral amygdala, posterior
piriform cortex, perirhinal cortex, and MD (Shimosaka et al., 1992).
Interestingly, perirhinal cortex (Tortorella et al., 1997) and
posterior piriform cortex (Halonen et al., 1994) appear to serve as
important relays in the seizure-propagating network, based on the fact
that inhibition within these regions impedes seizure generation. The
anatomical connections of MD suggest that it may represent another
critical component of the limbic seizure network. Because MD receives
input from numerous components of the limbic system, including the
piriform and rhinal cortices, it may integrate input from these
multiple components and link them with cingulate cortex and with
orbitofrontal cortex, with which MD has reciprocal connections
(Russchen et al., 1987; Giguere and Goldman-Rakic, 1988; Gower, 1989;
Carmichael and Price, 1995).
Furthermore, studies analyzing patterns of neurodegeneration after
seizures have reported that pronounced neuronal death occurs bilaterally in MD as a result of continuous generalized seizure activity evoked from AT (Shimosaka et al., 1992), systemic
administration of pilocarpine (Turski et al., 1986), and in humans
experiencing prolonged idiopathic hemiconvulsions (Mori et al., 1992).
These findings raise the possibility that seizure-induced pathology in
MD may contribute to short-term and/or long-term consequences of
prolonged or repeated seizures.
In view of the above evidence that MD is a target of seizure activity
triggered from piriform cortex, we investigated the functional role of
MD in limbic motor seizures. In the present study, we tested the
hypothesis that MD contributes to the propagation of limbic seizures
evoked from the piriform cortex. To accomplish this, we examined the
effects of focal inhibition of MD on seizures evoked from AT.
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MATERIALS AND METHODS |
Animals. All experiments were performed on male
Sprague Dawley albino rats (250-350 gm; Harlan Labs, Walkersville,
MD). The animals were housed in groups of three to four per cage under environmentally controlled conditions (12 hr light/dark cycle, lights
on between 8:00 A.M. and 8:00 P.M.; ambient temperature 23° ± 1°C), with food and water provided ad libitum. All
experiments were conducted during the light cycle in awake freely
moving animals and strictly conformed to all guidelines set forth by
the Georgetown University Animal Care and Use Committee.
Surgery. Rats were anesthetized with Equithesin (2.7 ml/kg,
i.p.) and placed in a Kopf stereotaxic apparatus. Two 22-gauge stainless steel guide cannulas (0.71 mm external diameter), one directed at the left AT and one directed at the left MD, were then
stereotaxically implanted and fixed to the skull with dental acrylic
and stainless steel jeweler's screws.
According to the deGroot coordinate system (Pellegrino et al., 1973),
the coordinates used for the final injection sites, with the incisor
bar 5 mm above the interaural line, were as follows: AT, 4 mm anterior
to bregma; 3.5 mm lateral to midline; and 6.5 mm ventral to dura; MD,
1.2 mm posterior to bregma; 1.0 mm lateral to midline; and 6.2 mm
ventral to dura (see Fig. 2A,B for
AT and MD sites, respectively).
Drugs. 2-Amino-7-phosphonoheptanoic acid (AP-7) (Research
Biochemicals, Natick, MA) was dissolved in a small volume (<10% of
final volume) of 1N NaOH, the pH was adjusted to 7.4 with
H3PO4, and the solution was then diluted
with distilled deionized water to a concentration of 0.5 mg/ml. A dose
of 500 pmol of AP-7 was injected in a volume of 225 nl over a duration
of 5 min. Bicuculline methiodide (Sigma, Saint Louis, MO) was dissolved
in saline at a concentration of 0.5 mg/ml; 118 pmol in 120 nl was
infused over 2 min 40 sec. Equithesin (used for anesthetic) was made by
combining chloral hydrate (4.3%), pentobarbital (0.9%), and
MgSO4 (2.1%) in propylene glycol-ethanol-water.
Vigabatrin (Marion Merrel Dow, Cincinatti, OH) was dissolved in saline
at a concentration of 100 mg/ml; 194 nmol in 250 nl was infused over a
duration of 5 min 33 sec. Muscimol (Natural Products Research
Chemicals) was dissolved in saline at a concentration of 0.1 mg/ml; 190 pmol in 240 nl was infused over a period of 5 min 20 sec. The sodium salt 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) (NovoNordisk, Malov, Denmark) was dissolved in saline at a
concentration of 1.0 mg/ml; 500 pmol in a volume of 159 nl was infused
over a duration of 3 min 45 sec.
Experimental procedures. After a postoperative recovery
period of at least 48 hr, each animal received a unilateral
microinfusion of a convulsant dose of bicuculline methiodide (118 pmol)
in AT with or without pharmacological pretreatment of MD. Glu receptor antagonists (AP-7 or NBQX), a GABAA receptor agonist
(muscimol), or an irreversible inhibitor of GABA transaminase
(vigabatrin) were focally microinfused in the ipsilateral MD before the
unilateral application of bicuculline to AT. For each infusion, a
28-gauge internal cannula (0.36 mm external diameter) was inserted
through the guide cannula while the rat was gently handheld, and the
drugs were then infused at a rate of 45 nl/min. The internal cannula was connected via polyethylene tubing to a 10 µl Hamilton syringe (Hamilton Co., Reno, NV) driven by a Sage infusion pump. After each
infusion, the internal cannula was left in place for 1 min to ensure
proper delivery of drug solution.
All animals were observed for convulsive activity for at least 2 hr
after the final infusion of bicuculline in AT. Seizure severity was
evaluated using the following scoring system modified from Racine
(1972): 0.5, facial clonus; 1, myoclonus of the contralateral forelimb;
2, bilateral forelimb clonus (with or without facial and jaw
clonus) lasting <15 sec; 3, bilateral forelimb clonus lasting
>15 sec; 4, rearing in addition to bilateral forelimb clonus; 5, rearing and loss of balance in addition to bilateral forelimb
clonus.
Histology. Brains were sectioned (50 µm) on a
freezing-stage microtome. Injection sites were then verified in cresyl
violet-stained sections viewed under light microscopy. Rats in which
cannula placements were not within AT were excluded from analysis. The locations of intrathalamic injection sites are shown in Figure 2B.
Evaluation of seizure response. Seizure analysis was
conducted according to three parameters: seizure incidence, seizure
severity, and seizure frequency. Seizure incidence is defined as the
percentage of animals that exhibit bilateral clonic seizures in an
experimental treatment group. Seizure severity is defined as the mean
of the maximum seizure scores attained by the animals in a group.
Seizure frequency is the number of clonic seizure episodes (score of 3, 4, or 5) occurring within 2 hr of the injection of bicuculline into AT.
A two-tailed t test or a repeated-measures ANOVA was used
for statistical evaluation of seizure frequency; comparisons were made
between each experimental treatment group and its corresponding control
group.
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RESULTS |
Figure 1 shows the autoradiographic
localization of 2DG in coronal sections through the brain of a
representative rat exhibiting recurrent limbic motor seizures (scores 4 and 5) in response to the microinjection of bicuculline methiodide (118 pmol) into AT. In Figure 1, the injection site can be seen in the
left column, middle row
(arrow). Several regions (including frontal, piriform, and
rhinal cortices) in the hemisphere ipsilateral to the injection exhibit
clear hypermetabolism, as evidenced by the high density of 2DG
accumulation. Most regions in the contralateral hemisphere were not
distinguishable from control rats (without seizures), with the
exception of MD, other midline thalamic nuclei, and substantia nigra,
all of which showed marked increases in accumulation of 2DG in both
hemispheres.
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Figure 1.
Pictures of autoradiographs showing accumulation
of 2DG (dark areas) in coronal sections of rat brain.
Bicuculline methiodide was injected 15 min before the intraperitoneal
injection of 2DG (18 mCi into 250 gm rats). Rats were anesthetized and
perfused 1 hr after injection of bicuculline. Arrow in
left column, middle row, points to AT
microinfusion site. Arrow in left column,
bottom row, points to MD.
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In control conditions (vehicle in MD), the seizures evoked by the
application of bicuculline methiodide (118 pmol in AT) consisted of
facial and forelimb clonus with rearing (and sometimes loss of balance)
in all animals (scores 4 and 5). Figure 2
shows the location of the injection sites. The AMPA receptor antagonist NBQX (500 pmol; n = 9), when unilaterally microinfused
into MD, protected 100% of the rats against seizures elicited from AT
(Fig. 3). Of the nine animals tested with
NBQX in MD, four animals exhibited no signs of seizure-related
activity, whereas the remaining animals exhibited only brief facial
twitching (four animals) or myoclonic jerks (one animal). Unilateral
focal microinfusion of the NMDA receptor antagonist AP-7 (500 pmol;
n = 7) into MD did not significantly alter the seizure
response evoked from AT (Fig. 4).
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Figure 2.
Sites of focal microinfusions. A,
Coronal representation depicting area of microinfusions within AT
(shaded area). B, Drawings of coronal
sections depicting location of microinfusions of muscimol or NBQX
within MD from which seizure protection was obtained
(filled circles). Open circles
represent sites where no seizure protection was obtained from these two
drugs. Numbers indicate anteroposterior distance
from bregma in millimeters.
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Figure 3.
Effect of focal microinfusion of an AMPA receptor
antagonist in MD. NBQX (500 pmol; n = 9) was
unilaterally microinfused into MD 5 min before microinfusion of
bicuculline (118 pmol) into the ipsilateral AT. Difference from
controls, *p < 0.05 (t test).
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Figure 4.
Effect of injection of an NMDA receptor antagonist
in MD. AP-7 (500 pmol; n = 7) was unilaterally
microinfused into MD 5 min before microinfusion of bicuculline (118 pmol) into the ipsilateral AT. Neither seizure severity nor seizure
frequency was modified by AP-7 in MD.
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In view of the distinct effects obtained with NBQX and AP-7, some of
the animals that received NBQX were subsequently tested with AP-7 (at
least 24 hr later), whereas other animals first tested with AP-7 were
later tested with NBQX. We found that in the same rats, with
application of drugs into the same site on separate occasions, the
treatment with NBQX consistently protected against seizures, whereas
the AP-7 treatments were without effect.
Unilateral pretreatment of MD with the GABAA receptor
agonist muscimol (190 pmol; n = 10) 5 min before the
injection of bicuculline in the ipsilateral AT suppressed the
development of limbic seizure activity in 8 of 10 animals. This
anticonvulsant effect was evidenced by a significant reduction in
seizure severity (for protected animals, the mean seizure score was
0.56 compared with 4.5 in the controls; 38% of these animals exhibited
no seizure-related activity), as well as seizure frequency compared
with controls (Fig. 5).
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Figure 5.
Effect of focal injection of GABAA
receptor agonist in MD. Muscimol (190 pmol; n = 10)
was microinjected into MD 5 min before microinjection of bicuculline
(118 pmol) into the ipsilateral AT. Difference from controls,
*p < 0.05 (t test).
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The anticonvulsant effects achieved with muscimol and NBQX were
strictly site specific, because no seizure protection was obtained in
six rats with injections placed 1-2 mm ventral or lateral to MD (for
locations, see Fig. 2B). Additionally, different injection sites within MD appeared to be equivalent for achieving seizure protection (data not shown). The focal pretreatment of MD alone
with the drugs tested did not induce changes in posture, spontaneous
behavior, or any other observable abnormalities.
To investigate the role of endogenous GABAergic transmission within MD
for controlling limbic motor seizures, vigabatrin (194 nmol) was
unilaterally microinfused into MD to elevate endogenous GABA locally by
irreversibly inhibiting GABA transaminase activity (Gale and Iadarola,
1980; Casu and Gale, 1981). To evaluate anticonvulsant effects,
bicuculline was applied to AT 2.5, 24, and 48 hr after the vigabatrin
pretreatment.
Pretreatment of MD with a single dose of vigabatrin resulted in
significant seizure protection when rats were tested at 2.5 and 24 hr
after microinfusion of vigabatrin into MD; recovery from the
anticonvulsant effects began by 48 hr, as indicated by seizure
frequency (Fig. 6A) and
the percentage of rats exhibiting seizures at the various time points
tested (Fig. 6B).
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Figure 6.
Effect of focal application of a GABA transaminase
inhibitor into MD. Vigabatrin (194 nmol) was unilaterally microinfused
into MD 2.5, 24, or 48 hr before microinfusion of bicuculline into the
ipsilateral AT. Seizure frequency (A) is shown as
mean ± SE for four to six animals per group. Statistical
comparisons using ANOVA were performed on the seizure frequency data
shown in A. Difference from controls,
*p < 0.05. Seizure incidence (percent of rats
exhibiting bilateral clonic seizures) is shown in B for
the same animals analyzed in A.
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DISCUSSION |
The results of this study demonstrate that the focal pretreatment
of MD with a GABAA receptor agonist or a Glu receptor
antagonist interferes with the development of focally evoked limbic
motor seizures. These findings suggest that excitatory transmission within MD is required for the development of limbic seizures and that
this crucial excitatory transmission is primarily glutamatergic. Moreover, the anticonvulsant effects obtained from MD were site specific, because injections placed 1-2 mm lateral or ventral to MD
did not attenuate seizure activity.
In contrast to the effects of the AMPA receptor antagonist NBQX, the
NMDA receptor antagonist AP-7 in MD had no effect on seizure activity.
This finding suggests that AMPA receptors within MD play a more
critical role than NMDA receptors in the transmission involved in the
genesis of limbic seizures elicited from piriform cortex.
Patel et al. (1988) reported that the bilateral focal injection of AP-7
into MD, at doses of 10-50 pmol, significantly protected against
seizures induced by the systemic administration of pilocarpine, a
muscarinic agonist. This finding is in contrast to our results with
AP-7 in MD. The differences between the outcomes of the two studies may
be a result of differences in the seizure models used and/or the
different rat strains used (i.e., Sprague Dawley vs Wistar).
Differences between these two rat strains in functional response to
subtype-specific Glu agonists have been noted previously (Maggio et
al., 1990).
The nonessential role of NMDA receptors in MD for development of
AT-evoked seizures stands in contrast to the role of NMDA receptors in
AT in the rat. Focal microinfusion of AP-7 (100 pmol  1.0 nmol)
into AT before the microinfusion of bicuculline, carbachol, or kainate
was found to prevent the initiation of convulsions from AT (Piredda and
Gale, 1986b), indicating that NMDA receptor-mediated transmission in AT
is required for triggering seizures from this site in the rat. Thus,
the profile of critical neurochemical substrates within AT differs from
that in MD.
On the other hand, the pharmacological profile that we have described
for MD is similar to that described previously for the posterior
piriform cortex, another site critical for the relay of AT-evoked
seizures. The posterior piriform cortex is an important target of
excitatory output from AT and a key component of the network
responsible for the initiation and propagation of seizure activity
generated from this site. In posterior piriform cortex, as in MD,
blockade of AMPA receptors (with NBQX), but not NMDA receptors (with
AP-7), prevents the development of seizures evoked from AT (Halonen et
al., 1994).
Anatomical tracing studies have shown that MD is richly connected to
several structures that may constitute a network for the propagation of
limbic motor seizures elicited from AT. MD receives direct afferents
from AT itself (Sahibzada et al., 1992) and from three primary target
regions of AT: piriform cortex, entorhinal cortex, and perirhinal
cortex (Russchen et al., 1987; Steriade et al., 1987; Gower, 1989;
Kuroda et al., 1992). Perirhinal cortex, like MD, is a crucial relay
for AT-evoked seizures (Tortorella et al., 1997), raising the
possibility that perirhinal cortex and MD may be part of a core
seizure-propagating loop activated by AT. Alternatively, MD may
regulate multiple neural loops and coordinate their coactivation in
parallel. Considerable excitatory connections also exist between MD and
basolateral amygdala (Van Vulpen and Verwer, 1989), and this circuitry
may contribute to the unusually rapid transfer of kindling between AT
and amygdala (McIntyre and Goddard, 1973).
In addition to its associations with limbic structures, MD is linked
directly and indirectly (e.g., via prefrontal cortex) with basal
ganglia structures that regulate the threshold for limbic motor
seizures. Such structures include substantia nigra and entopeduncular
nucleus (Kuroda and Price, 1991), which when inhibited bilaterally
exert anticonvulsant actions in several seizure models (Gale, 1992),
and striatum, which suppresses seizures when disinhibited or stimulated
(Cavalheiro et al., 1987; Turski et al., 1987). Activation of
corticostriatal projections, which in turn stimulate striatal GABAergic
projections to substantia nigra, could mediate the influence of MD on
seizure susceptibility. However, the fact that we blocked AT seizures
with unilateral inhibition of MD argues against this possibility,
because the unilateral inhibition of substantia nigra is not sufficient
to attenuate AT-evoked seizures (Maggio and Gale, 1989).
The limbic network by which MD influences seizure propagation may share
certain crucial components with the network that supports long-term
recognition memory. MD, perirhinal cortex, and orbitofrontal cortex
have been shown to be critical substrates of recognition memory, based
on recording studies (Fahy et al., 1993a,b; Miller and Desimone, 1994)
and on the observations that selective bilateral lesions of each of
these areas result in profound memory impairment in experimental
animals (Aggleton and Mishkin, 1983; Zola-Morgan and Squire, 1985;
Bachevalier and Mishkin, 1986; Meunier et al., 1993; Suzuki et al.,
1993; Mumby and Pinel, 1994). Furthermore, seizure-induced damage to MD
has been correlated with deficits in radial arm maze learning
(Persinger et al., 1994). In view of the projections from perirhinal
cortex to MD and the reciprocal connections between MD and
orbitofrontal cortex, it is likely that MD serves to link these
circuits into a coordinated network subserving recognition memory. MD
may similarly serve to link the neural loops subserving seizure
propagation in frontolimbic networks. Via its connections with amygdala
and its ability to regulate prefrontal neurons that project to
piriform, perirhinal, and entorhinal cortices, MD may control the
extent to which the activity in the network becomes synchronized.
Hypersynchrony in this network, as occurs with propagated seizures,
would be expected to be incompatible with the more controlled neural
signaling important for encoding memory (Fahy et al., 1993a,b).
Moreover, suppression of this network, as may occur during postictal or
interictal periods, could also impede the mnemonic function of this
circuitry. Thus, seizure-evoked acute and/or chronic alterations in MD
circuitry may contribute to the memory impairment associated with
complex partial seizures.
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FOOTNOTES |
Received June 9, 1998; revised Aug. 5, 1998; accepted Aug. 7, 1998.
This work was supported by National Institutes of Health Grants
T32HD07549, NS28130, and NS20576. We thank Dr. Francesco Fornai and
David Dybdal for helpful discussions throughout the course of these
studies and Laura Williams for help with the preparation of this
manuscript.
Correspondence should be addressed to Dr. Karen Gale, Department of
Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road
N.W., Washington, DC 20007.
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Abstract
Introduction
