Epilepsy Research (2008) 78, 102—116
journal homepage: www.elsevier.com/locate/epilepsyres
Pathology and pathophysiology of the
amygdala in epileptogenesis and epilepsy
Vassiliki Aroniadou-Anderjaskaa,1, Brita Fritscha,c,1,
Felicia Qashub, Maria F.M. Bragaa,b,∗
aDepartment of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
bNeuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
cEpilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD,
Received 15 August 2007; received in revised form 20 November 2007; accepted 30 November 2007
Available online 15 January 2008
common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE),
which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to
epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays
a major role in the initial pathological and pathophysiological damage. This initial damage is
followed by a latent period, during which there is no seizure activity, yet a number of patho-
physiological and structural alterations are taking place in key brain regions, that culminate in
the expression of epilepsy. The process by which affected/injured neurons that have survived
the acute insult, along with well-preserved neurons are progressively forming hyperexcitable,
epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms
of epileptogenesis is crucial for the development of therapeutic interventions that will prevent
the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a tem-
poral lobe structure that is most well known for its central role in emotional behavior, also plays
a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on
the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients,
and in animal models of TLE. In addition, because a derangement in the balance between gluta-
matergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic
neuronal circuits, we also review the information available on the role of the glutamatergic
and GABAergic systems in epileptogenesis and epilepsy in the amygdala.
Published by Elsevier B.V.
Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are
∗Corresponding author at: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences,
4301 Jones Bridge Road, Bethesda, MD 20814, USA. Tel.: +1 301 295 3524.
E-mail address: email@example.com (M.F.M. Braga).
1These authors contributed equally.
0920-1211/$ — see front matter. Published by Elsevier B.V.
Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy 103
Is amygdala important in epilepsy?.......................................................................................
Amygdala pathology in epilepsy..........................................................................................
The role of the glutamatergic system ....................................................................................
The role of the GABAergic system........................................................................................
Summary and concluding remarks........................................................................................
Induction of epileptogenesis.........................................................................................
The process of epileptogenesis......................................................................................
The GABAergic system in the epileptic amygdala....................................................................
The glutamatergic system in the epileptic amygdala ................................................................
Epilepsy is one of the most common, chronic neurological
disorders, which is characterized by recurrent, spontaneous
brain seizures. For some types of epilepsy, the etiology is
unknown and may involve genetic predisposition (idiopathic
epilepsy; Hirose et al., 2000; Berkovic and Scheffer, 2001),
while other types of epilepsy are secondary to another dis-
ease, or to an acute brain insult, such as stroke, status
epilepticus (SE), head injury, or exposure to neurotoxic sub-
stances (acquired epilepsy; Annegers, 1993; Anderson et al.,
1999; Herman, 2002). In acquired epilepsy where an acute
brain insult has been the etiological factor, the symptoms
of epilepsy often appear after a seizure-free period fol-
lowing the acute injury (Angeleri et al., 1999; Gupta and
Gupta, 2006; Pagni and Zenga, 2006; Statler, 2006). In trau-
matic brain injury, the incidence of such late post-traumatic
seizures ranges from 5% to 18.9% in civilian populations
and 32% to 50% in military personnel (Salazar et al., 1985;
Bushnik et al., 2004). The duration of the latent, seizure-
free period can vary widely, from months to years (Treib
et al., 1996; Benardo, 2003). This latent period offers the
opportunity for therapeutic intervention that may prevent
the development of epilepsy, or reduce the severity of
the developing disease. The development of regimens that
will prevent epilepsy is of vital importance, particularly
considering that post-traumatic epilepsy is often refrac-
tory to current anticonvulsant therapies (Semah et al.,
1998). However, for effective treatments to be developed,
the alterations that occur in the structure and function
of neuronal networks, which lead to the expression of
epilepsy must first be understood. The process whereby,
after an acute brain insult, pathological and pathophysio-
logical alterations gradually occur in certain brain regions,
leading to the expression of epilepsy, is referred to as epilep-
Temporal lobe structures, notably the hippocampus, the
amygdala, and the piriform cortex are most susceptible
to seizurogenic and epileptogenesis-triggering brain insults;
accordingly, temporal lobe epilepsy (TLE) is the most com-
mon form of epilepsy (Engel, 1989). There is extensive
literature on the pathology and pathophysiology of the hip-
pocampus in epilepsy, and information on the hippocampal
alterations associated with epileptogenesis is also becom-
ing available (DeLorenzo et al., 2006; El-Hassar et al., 2007;
Lahtinen et al., 2006; Lukasiuk et al., 2006; McNamara et
al., 2006; Raol et al., 2006). The amygdala, on the other
hand, has received much less attention, despite the evi-
dence that its role in epilepsy is at least as important as
that of the hippocampus. The purpose of the present arti-
cle is to review the current knowledge on the pathology
and pathophysiology of the amygdala in epileptogenesis and
epilepsy. Emphasis will be placed on the alterations in the
glutamatergic and GABAergic systems, since an imbalance in
the function of these two neurotransmitter systems appears
to be ‘‘the final common pathway’’ by which molecu-
lar/biochemical, structural and pathophysiological changes
contribute to hyperexcitability.
Is amygdala important in epilepsy?
The amygdala is most well recognized for its central role in
emotional behavior, as well as in the modulation of cogni-
tive functions (LeDoux, 1992; Davis, 1994; McGaugh et al.,
1996; Fanselow and Gale, 2003; Sah et al., 2003). What is
the evidence that the amygdala also plays a central role in
epilepsy? In TLE, in addition to hippocampal damage, exten-
sive neuropathology is also present in the amygdala in a
significant subpopulation of patients (Cendes et al., 1993b;
Saukkonen et al., 1994; Pitkanen et al., 1998). The epileptic
focus, in TLE, resides in the amygdala, or the hippocampus,
or in both regions (Quesney, 1986; Isokawa-Akesson et al.,
1987; Dewar et al., 1996; Pitkanen et al., 1998; Morimoto et
al., 2004). Accordingly, although hippocampal resection of
varying degrees is often necessary in drug-refractory TLE,
in some cases amygdalectomy alone is sufficient to elimi-
nate seizures (Feindel and Rasmussen, 1991; Jooma et al.,
1995; Wieser, 2000). Since the amygdala modulates cogni-
tive functions and plays a central role in emotional behavior
(LeDoux, 1992; Davis, 1994; McGaugh et al., 1996; Fanselow
and Gale, 2003; Sah et al., 2003) and affective disorders
(Drevets, 1999; Rauch et al., 2000; Chen et al., 2006), as
well as in sexual behavior (Kostarczyk, 1986; Salamon et al.,
2005), amygdala dysfunction in TLE is important not only
for its role in the generation of seizures, but also for its
role in the emotional and cognitive disorders (Kanner, 2006;
104V. Aroniadou-Anderjaska et al.
Swinkels et al., 2006; Briellmann et al., 2007; Richardson et
al., 2007; Seethalakshmi and Krishnamoorthy, 2007), and in
sexual dysfunction (Herzog et al., 2003; Harden, 2006) that
often accompany epilepsy.
Studies in animals have suggested that the amygdala is
even more prone to generating seizure activity than the hip-
pocampus (Goddard, 1967; Kairiss et al., 1984; Racine et
al., 1988). Thus, kindling develops much faster by repeated
(Goddard, 1967; McIntyre and Racine, 1986), and interic-
tal discharges tend to be initiated in the amygdala/piriform
cortex regardless of the site of kindling (Kairiss et al., 1984;
Racine et al., 1988). Additional evidence for a central role of
the amygdala in the generation and spread of seizure activ-
ity comes from studies on the mechanisms by which nerve
agents induce brain seizures. These studies have demon-
strated that, after exposure to toxic levels of the nerve
agent soman, the amygdala displays the earliest and most
rapid increase in extracellular glutamate, suggesting an
early involvement of the amygdala in the development of
soman-induced seizures (Lallement et al., 1991a, 1991b).
Moreover, after nerve agent exposure, the amygdala dis-
plays the most extensive seizure-induced damage (Shih et
al., 2003), which is consistent with its exceptionally high
susceptibility to seizurogenic insults.
From the more than 10 nuclei that amygdala is com-
posed of (McDonald, 2003; Sah et al., 2003), the basolateral
nucleus of the amygdala (BLA) plays the most important role
in the initiation and spread of seizures. Activation of the BLA
is primarily responsible for the generation of widespread
SE, even in animal models where seizures are evoked in
extra-amygdalar regions (White and Price, 1993a, 1993b).
Furthermore, prolonged electrical stimulation triggers SE
more readily when the stimulation is applied to the BLA
than to the central and medial amygdala, or to the adjacent
piriform cortex (Mohapel et al., 1996).
Thus, both clinical findings and animal studies indicate
and the symptomatology of epilepsy. The basolateral region
of the amygdala appears to be most susceptible to seizure
Amygdala pathology in epilepsy
Amygdala damage is often present in TLE, regardless of the
etiology of the disease. It can be present in patients with no
prior history of SE (Margerison and Corsellis, 1966; Bruton,
1988; Hudson et al., 1993), or it may develop, with vari-
able timecourses, after SE (Fowler, 1957; Norman, 1964).
Although in many cases amygdala damage is co-present with
damage in other brain regions and particularly the hip-
pocampus (Bruton, 1988; Guerreiro et al., 1999), it can also
be an isolated pathological finding in TLE patients (Hudson
et al., 1993; Miller et al., 1994; Guerreiro et al., 1999).
Magnetic resonance imaging has revealed that a common
pathology of the amygdala in TLE is atrophy (reduced volume
associated with neuronal loss), which can range from 10%
to 57% volume reduction (Pitkanen et al., 1998). Although
amygdala atrophy can be present bilaterally, most often it
coincides with the hemisphere that harbors the epileptic
focus (Cendes et al., 1993b, 1993c, 1993d; Saukkonen et
al., 1994; Van Paesschen et al., 1996). The severity of the
atrophy does not appear to correlate with the frequency
of seizures, the age of the patient, or the age of onset
of epilepsy (Cendes et al., 1993a; Guerreiro et al., 1999;
Salmenpera et al., 2001). A correlation of amygdala atro-
phy with the chronicity of epilepsy has been found in some
studies (Kalviainen et al., 1997; Bernasconi et al., 2005),
however this is not a consistent finding (Cendes et al.,
1993c; Guerreiro et al., 1999; Salmenpera et al., 2001).
A more severe amygdala atrophy may be associated with
a history of prolonged febrile convulsions (Cendes et al.,
1993a; Salmenpera et al., 2001), but this correlation has
not been found consistently (Bernasconi et al., 2005). Func-
tional consequences that accompany significant amygdala
damage in TLE patients include experience of fear during
seizures (Cendes et al., 1994) and prolonged postictal con-
fusion (Guerreiro et al., 1999).
The regions of the amygdala that present the most severe
damage (neuronal loss and gliosis), in TLE patients, are the
lateral and basal nuclei (Meyer et al., 1955; Margerison
and Corsellis, 1966; Hudson et al., 1993; Pitkanen et
al., 1998). Similarly, in non-human primates, the basolat-
eral portions of the amygdala are the most susceptible
to seizure-induced damage (Meldrum and Brierley, 1973;
Wasterlain et al., 1996; Pitkanen et al., 1998). In rat mod-
els of SE, the greatest cell loss in the amygdala is also
observed in portions of the lateral and basal nuclei, as
well as in the deep layers of the anterior cortical and
medial nuclei, and the posterior cortical nucleus (Tuunanen
et al., 1996). Interestingly, Tuunanen et al. (1997) found
that somatostatin-immunoreactive neurons (the majority of
which are GABAergic neurons; McDonald and Pearson, 1989;
McDonald and Mascagni, 2002) in the medial division of
the lateral nucleus and magnocellular division of the basal
nucleus, in the rat, are most susceptible to damage even
by a relatively small number of kindling-induced seizures,
while overall the magnocellular division of the basal nucleus
appears well preserved even after SE (Tuunanen et al., 1996,
1997). Our observations in rats, after kainic acid-induced
SE, also show a well-preserved magnocellular division in the
basal nucleus, despite extensive damage in other regions
of the amygdala, as well as in the piriform cortex (Fig. 1).
Thus, it appears that a subpopulation of inhibitory neurons
in an important projection nucleus of the amygdala is very
susceptible to seizure-induced damage, while projection
neurons remain relatively intact. This would facilitate the
spread of seizures from the damaged, epileptic amygdala to
other brain regions (for a discussion on this implication see
Tuunanen et al., 1996, 1997).
Importantly, seizure-induced cell loss in the amygdala
and other brain areas is accompanied by neurogenesis; this
has been observed at 24h after the last seizures induced by
a GABAAantagonist, injected systemically for 14 consecu-
tive days, in rats (Park et al., 2006). Neurogenesis appears
to be an independent effect of recurrent epileptic seizures
rather than a consequence of neuronal cell death, as there
is no significant correlation between the severity of cell loss
and the extent of neurogenesis (Park et al., 2006). Whether
the appearance of newborn neurons signifies a potential
for reorganization of the amygdala, and whether it would
contribute to the pathogenesis of epilepsy, or to a gradual
recovery of pathology and function after the initial insult,
Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy 105
piriform cortex-amygdala region, at different time points after kainic acid-induced SE (KA-SE), and from control animals. Sections
are approximately −2.12mm from bregma (after Paxinos and Watson, 1998). Upper images (A) demonstrate the extensive edema
present at 3 days after KA-SE in the piriform cortex and the amygdala (outlined with dotted line). (B) Edema is no longer present at
24 days after KA-SE, while dramatically severe neuronal loss is evident in the piriform cortex (small arrows). The cortical nucleus
of the amygdala is also damaged but to a lower extent (*). The magnocellular division of the basal nucleus of the amygdala (large
arrows) remains well preserved at both time points after KA-SE. Scale bar: 500?m.
Photomicrographs of cresyl violet-stained coronal sections (section thickness: (A) 35?m and (B) 16?m) from the rat
remains to be determined. In the studies by Tuunanen et al.
(1996), there were no significant differences in the distribu-
tion or severity of amygdala damage (cell loss) at 2 days or
2 weeks after kainic acid-induced SE, in rats. Thus, at least
within this timeframe of SE-induced epileptogenesis, there
are no significant changes in the distribution or the extent
of neuronal degeneration and regeneration in the amygdala,
in this model.
When pathological alterations in the rat amygdala were
examined with quantitative MRI, after SE induced by amyg-
dala stimulation, it was found that much of the initial
damage was associated with edema, which, for the most
part, was reversed by 9 days after SE (Nairismagi et al.,
2004). However, secondary neuronal pathology appeared
and progressed with time, in the amygdala and other
brain regions (Nairismagi et al., 2004). After kainic acid-
induced SE, in rats, increased MRI signal intensity, suggesting
the presence of edema, was observed bilaterally in the
amygdala and the piriform cortex, immediately after the
sustained seizures, as well as 24h later (Nakasu et al.,
1995). This early edema is also observed with histolog-
ical methods (see Fig. 1A). Reversible increases in MRI
106 V. Aroniadou-Anderjaska et al.
signal intensity within the medial temporal lobe, sugges-
tive of edema, is also seen in TLE patients after prolonged
seizure activity (Chan et al., 1996). The significance of
this largely reversible acute tissue damage, and whether it
precedes and is predictive of (further) subsequent patho-
logical and pathophysiological alterations, is unclear. In the
kainic acid-induced SE model, the area of hyperintensity in
diffusion-weighted MRI images (signifying the presence of
edema) was concordant with the histologic distribution of
neuronal pyknosis and neuropile vacuolation (Nakasu et al.,
1995). However, others have found that this early disruption
in water homeostasis does not correlate significantly with
the extent of the long-term pathological damage and the
severity of the spontaneous, recurrent seizures (Nairismagi
et al., 2004). Finally, as is the case with the hippocampus
(Andre et al., 2001; Brandt et al., 2003; Francois et al.,
2006), it appears that pathological damage (early or late) of
the amygdala does not correlate well with the development
of epileptogenesis and the severity of epilepsy. Thus, the
development of spontaneous seizures after extended amyg-
dala kindling was not accompanied by neurodegeneration in
either the amygdala, or the CA1 and CA3 hippocampal areas
(Brandt et al., 2004). Similarly, in rats becoming epileptic
after SE induced by hippocampal stimulation, there were no
significant pathological, neurodegenerative changes in the
amygdala, despite the presence of pronounced pathophys-
iological alterations in the basal amygdala (Mangan et al.,
In summary, amygdala atrophy is often present in TLE
patients, but clear correlations of the presence of amyg-
dala pathology with other parameters of the disease that
would help us understand the causes and the consequences
of amygdala atrophy are still not evident. In both human
patients and animal models of epilepsy, certain regions of
the amygdala, and in particular the basolateral nucleus are
most susceptible to damage. Although pathological dam-
age of the amygdala is prominent in some animal models
of epilepsy, pathophysiological alterations that produce or
contribute to the generation of spontaneous seizures and
the expression of epilepsy can be present without evidence
for concomitant presence of pathological damage.
The role of the glutamatergic system
It is well understood that excessive glutamatergic activity
plays a key role in both the induction of neuronal pathol-
ogy that can lead to hyperexcitability and epilepsy, and the
expression of hyperexcitability and epilepsy. Thus, in exper-
imental models, when status epilepticus (SE) is induced by
injections of kainic acid, the initiation of seizures is obvi-
ously due to activation of the kainate subtype of glutamate
receptors; the resulting neuronal damage is due to excessive
glutamate release associated with the epileptic seizures (Liu
et al., 1997; Sherwin, 1999; Pena and Tapia, 1999; Ueda et
al., 2002). When SE is triggered by administration of the
muscarinic agonist pilocarpine, or by acetycholinesterase
inhibitors, although excessive cholinergic activity is the
initial trigger of epileptic seizures, it is glutamatergic
activity that reinforces and sustains seizures, and is ulti-
mately responsible for neuronal damage (Wade et al.,
1987; Lallement et al., 1991a, 1991b, 1992; McDonough and
Shih, 1997; Smolders et al., 1997). Similarly, in humans, in
acquired epilepsy due to an acute brain insult, such as trau-
matic brain injury, stroke, or status epilepticus, excessive
glutamate release plays a central role in the resulting brain
damage (Choi, 1988; Choi and Rothman, 1990; During and
Spencer, 1993; Arundine and Tymianski, 2004; Yi and Hazell,
2006). Glutamate excitotoxicity is due to overstimulation of
glutamate receptors producing excessive neuronal depolar-
ization, which is accompanied by an overwhelming increase
in free intracellular calcium, entering via glutamate recep-
tor/channels and voltage gated calcium channels, as well as
released from intracellular stores; the calcium-dependent
signaling pathways that are subsequently activated lead to
neuronal dysfunction (physiopathology), and/or pathology
(alterations in morphology/structure), or death (Choi, 1988;
Pal et al., 1999; Pal et al., 2000; DeLorenzo et al., 2006;
McNamara et al., 2006).
After the initial damage from an acute brain insult,
there is a ‘‘silent’’, latent period before the expression of
epilepsy. A number of alterations occur in surviving neu-
rons during this period of epileptogenesis (Kim et al., 2007;
Gorter et al., 2006; DeLorenzo et al., 2006; Lahtinen et
al., 2006; McNamara et al., 2006; Lukasiuk et al., 2006;
El-Hassar et al., 2007) which eventually lead to the gen-
eration of spontaneous, recurrent seizures. Glutamatergic
activity does not appear to play an important role in the
progression of epileptogenesis, since antiepileptic drugs,
which suppress excitatory synaptic transmission, either
directly or by increasing GABAergic inhibitory activity, fail to
(Halonen et al., 2001; Loscher, 2002; Francois et al., 2006).
However, when epilepsy has developed, the major charac-
teristic of the hyperexcitable neuronal circuits is excessive
glutamatergic activity, associated with a derangement in
the balance between glutamatergic and GABAergic synaptic
transmission (Bernard, 2005; El-Hassar et al., 2007).
As in other brain regions, the glutamatergic system in
the amygdala also plays a central role in the induction of
neuronal damage and epileptogenesis, as well as in the
expression of epilepsy. In kainate- or pilocarpine-induced SE
animal models, pretreatment with NMDA receptor antag-
onists prevents the induction of epileptogenesis, despite
the lack of a significant effect on the SE itself (Stafstrom
et al., 1993; Rice and DeLorenzo, 1998). However, NMDA
receptor antagonists do not inhibit epileptogenesis if admin-
istered after the acute brain insult (Brandt et al., 2003), and
they are also weak anticonvulsants when epilepsy has devel-
oped (McNamara et al., 1988; Sato et al., 1988; Morimoto
et al., 2004). Some of the information on the role of the
glutamatergic system in epileptogenesis and epilepsy in the
amygdala comes from kindling experiments, where repeated
electrical stimulation of a seizure-susceptible brain region
lowers the threshold for seizures, and eventually triggers
generalized, stage 5 seizures; spontaneous seizures also
often occur after extended kindling (Brandt et al., 2004). In
gered by an acute brain insult, but rather it is induced and
reinforced incrementally by repeated stimulation. Kindling
induced by repeated electrical stimulation of the amygdala
requires activation of AMPA receptors (Namba et al., 1994;
Rogawski et al., 2001). Kindling can also be produced by
application of glutamate. Thus, overactivation of glutamate
Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy 107
receptors by repeated focal application of glutamate into
the amygdala has a kindling-like effect (‘‘glutamate kin-
dling’’; Mori and Wada, 1987; Croucher and Bradford, 1989).
Antagonists of NMDA receptors retard or prevent amygdala
kindling induced either by repeated electrical stimulation
(Gilbert, 1988; McNamara et al., 1988; Sato et al., 1988;
Holmes et al., 1990; Morimoto et al., 1991), or by glutamate
application (Croucher and Bradford, 1990). In agreement
with these results, amygdala kindling is more difficult to
induce in transgenic mice expressing high neuronal levels
of NR2D, which produces lower conductance NMDA recep-
tor complexes with reduced affinity for glutamate (Bengzon
et al., 1999). Taken together, these findings are consistent
with the view that NMDA receptor/channels provide a major
route for calcium influx during induction of epileptogenesis.
The pathophysiological alterations that take place in
the amygdala as epileptogenesis is underway are largely
unknown, and it is generally assumed that the alterations
seen in epilepsy have developed gradually during the course
a more or less linear fashion during the course of epileptoge-
nesis, or does the timing pattern of their development result
epileptogenesis? Answers to these questions are necessary
for the development of successful pharmacological inter-
ventions that will inhibit epileptogenesis. It should be noted
in this regard, that in the CA1 hippocampal pyramidal cells,
the balance between glutamatergic excitation and GABAer-
gic inhibition is actually tilted towards more inhibition at
3—5 days after pilocarpine-induced SE in rats, compared to
controls. This is reversed, with glutamatergic drive increas-
ing significantly to generate interictal activity by 7—10 days
after SE (El-Hassar et al., 2007). These observations suggest
that the dynamics between major neurotransmitter systems
can differ dramatically at different stages of epileptogene-
When epilepsy has developed, alterations in glutamater-
gic synaptic transmission are evident in the amygdala. In
brain slices from rats becoming epileptic after pilocarpine-
induced SE, large amplitude depolarizing postsynaptic
potentials (along with reduction of inhibition; see next sec-
tion) were evoked in lateral amygdala neurons; increased
spontaneous field activity was correlated with intracellu-
larly recorded neuronal firing that was blocked by glutamate
receptor antagonists (suggesting that it was induced synap-
tically), while the intrinsic properties of neurons were
not significantly altered (Benini and Avoli, 2006). Simi-
larly, basal amygdala neurons from rats becoming epileptic
after SE induced by stimulation of the hippocampus, display
hyperexcitability characterized by multiple action poten-
tial bursts in response to stimulation of the stria terminalis
(Mangan et al., 2000). In brain slices from kindled rats,
basolateral amygdala neurons display large amplitude AMPA
and NMDA receptor-mediated EPSPs, which can be evoked
with lower stimulus intensities as compared to control rats
(Rainnie et al., 1992; Shoji et al., 1998). Although there
are impairments also in GABAergic transmission, enhanced
glutamatergic transmission in the BLA of kindled rats is
still present when GABAAreceptors are blocked (Rainnie et
al., 1992), which is indicative of alterations in components
that are directly involved in glutamatergic transmission.
Recordings of whole-cell currents from basolateral amyg-
dala neurons have shown that the rise time of evoked
CNQX- and AP5-sensitive EPSCs, and the decay time con-
stant of evoked CNQX-sensitive EPSCs are shorter in kindled
rats, suggesting that excitatory synapses at the proximal
dendrites and/or the somata of kindled neurons may con-
tribute more effectively to the generation of evoked EPSCs
than those at distal dendrites (Shoji et al., 1998). In addi-
tion, the frequency and amplitude of spontaneous EPSCs
are increased in basolateral amygdala neurons from kindled
rats, in tetrodotoxin-containing medium with either normal
or low concentration of calcium, suggesting an increased
probability of presynaptic glutamate release (Shoji et al.,
1998). The increases in the amplitudes of spontaneous and
evoked EPSCs and in the frequency of spontaneous EPSCs
may contribute to the epileptiform discharges in kindled
amygdala neurons (Shoji et al., 1998). The intrinsic prop-
erties of basolateral amygdala neurons (resting membrane
potential, apparent input resistance, current—voltage rela-
tionship of the membrane, number of action potentials
as the threshold, amplitude, and duration of action poten-
tials) are not altered by kindling (Rainnie et al., 1992; Shoji
et al., 1998).
In rats where epilepsy developed after kainic acid-
induced SE, evoked field potentials in the BLA contained
a much greater number of population spikes compared to
control rats, and these alterations were not only due to
reduction of inhibition, as the differences from the control
rats were also evident in the presence of GABAA receptor
antagonists (Smith and Dudek, 1997). We have made similar
observations of burst-like, extracellular spiking activity in
field potentials recorded from rats displaying spontaneous
recurrent seizures, at 7 days after kainic acid-induced SE
(Fig. 2). Increased neuronal discharges can also be seen in
the field potentials recorded from epileptic rats, at 7—8
weeks after SE induced by stimulation of the lateral amyg-
dala (see Figure2Fig. 2C, baseline, in Niittykoski et al.,
2004), although it was noted in that study that the ampli-
tudes and slopes of the field potentials in the lateral and
basal amygdala of the epileptic rats were reduced com-
pared to controls (Niittykoski et al., 2004). We, too, have
observed that higher stimulus intensities are required to
evoke field potentials in the BLA of epileptic rats, after
kainic acid-induced SE, at least when recordings are made
up to 10 days after SE; the reduction of the field responses
appears to relate to the severity of amygdala damage, as
revealed by histological techniques (Qashu and Fritsch et
al., unpublished data). These findings are not in discord with
the larger EPSPs recorded intracellularly from the epileptic,
or kindled amygdala. Thus, when recordings are obtained
from single neurons, these are the surviving neurons that
participate in the generation of epileptic seizures. When
neuronal population responses are sampled using extracellu-
lar, field potential recordings, the extent of the damage/cell
loss is also ‘‘sampled’’; weaker population responses can
be expected when neuronal damage is extensive and not
limited to interneurons.
An area that deserves attention — in relation to the
pathophysiology of the amygdala in epileptogenesis and
epilepsy — is the role of kainate receptors, and, in partic-
ular, the kainate receptors that contain the GluR5 subunit
(GluR5KRs). In rats, in contrast to the hippocampus which
108 V. Aroniadou-Anderjaska et al.
nal capsule in the BLA region of in vitro brain slices. In rats
which had undergone status epilepticus (SE) by systemic injec-
tion of kainic acid, eliciting field potentials required higher
stimulus intensities compared to control rats (this is due at
least in part to amygdala damage; see text), and the field
potentials in these rats — which are already epileptic by day
7 — contained multiple, low-amplitude population spikes. Bath
application of the GluR5 agonist ATPA, which excites principal
cells in the BLA (Gryder and Rogawski, 2003) and reduces evoked
GABAAreceptor-mediated inhibition (Braga et al., 2003), pro-
duced epileptiform activity in both the control rats and the
SE-rats. Epileptiform activity was always stronger in the control
rats compared to the SE-rats, probably due to the neuronal dam-
age in the SE-rat. It is noteworthy however that the SE-damaged
amygdala can still sustain strong epileptiform activity.
Field potentials evoked by stimulation of the exter-
shows only weak expression of the GluR5 gene, the amyg-
dala displays a markedly high expression of this kainate
receptor subunit (Bettler et al., 1990; Li et al., 2001; Braga
et al., 2003). The location and function of GluR5KRs in
the BLA were revealed recently with electrophysiological
studies; on principal cells, GluR5KRs participate in gluta-
matergic excitation (Gryder and Rogawski, 2003), while on
GABAergic interneurons they are present both on postsy-
naptic sites where they participate in the glutamatergic
excitation of interneurons, and on presynaptic GABAergic
terminals where they inhibit GABA release (Braga et al.,
2003, 2004a; Aroniadou-Anderjaska et al., 2007). Interest-
ingly, a presynaptic facilitation of GABA release that has
been seen with very low concentrations of a GluR5 agonist
(ATPA; Clarke et al., 1997) in 15—22-day-old rats (Braga et
al., 2003), is no longer present in young adult and adult
rats, where only inhibition of GABA release is observed
(Aroniadou-Anderjaska et al., unpublished data). The net
effect of GluR5KR activation in the rat BLA, in vitro, as we
have seen in field potential and current-clamp whole cell
recordings, is an overall increase in the BLA neuronal and
circuitry excitability, with induction of spontaneous epilep-
tiform bursting. Furthermore, when ATPA is administered to
rats in vivo by intravenous infusion, or by direct applica-
tion into the amygdala, it induces clonic seizures and has
an epileptogenic effect (Rogawski et al., 2003; Kaminski et
al., 2004). These effects of ATPA are blocked by GluR5KR
antagonists. Moreover, GluR5KR antagonists do not block
only seizures induced by selective activation of GluR5KRs;
Smolders et al. (2002) have demonstrated that GluR5KR
antagonists prevent the initiation (induction) and block the
expression of limbic seizures induced by electrical stimu-
lation, or by administration of the muscarinic cholinergic
receptor agonist pilocarpine. It is important therefore to
delineate the role that GluR5KRs play in the initiation and
progression of epileptogenesis, and in the expression of lim-
bic epilepsy. The importance of GluR5KRs increases further
when it is considered that GluR5 antagonists are unlikely to
2004) because (1) at concentrations that prevent the induc-
antagonists have no effect on normal excitatory synaptic
transmission (Smolders et al., 2002) and (2) the distribution
of GluR5KRs in the brain is relatively limited (Bettler et al.,
1990; Li et al., 2001; Braga et al., 2003), and, therefore,
their blockade should not significantly affect brain function.
The role of the GABAergic system
In hyperexcitable, epileptic neuronal circuits, regardless
of the underlying mechanisms that have led to hyperex-
citability, the characteristic end result is a derangement in
the balance between excitatory and inhibitory activity. This
imbalance could be associated with molecular and/or func-
tional alterations in components that are directly involved in
glutamatergic transmission, or glutamatergic activity could
be indirectly enhanced due to impairment in the GABAergic
system, or both. In the previous section we examined the
role of the glutamatergic system in the induction of epilep-
togenesis, and reviewed the evidence indicating alterations
in glutamatergic transmission in the epileptic amygdala.
In this section, we will examine the role of the GABAer-
gic system in epileptogenesis, and the evidence suggesting
impairment in the function of the GABAergic system in the
amygdala when epilepsy has developed.
It is well established that the GABAergic system con-
trols neural activity and can suppress epileptic activity.
For example, in animals kindled by amygdala stimulation,
GABAAagonists have potent anticonvulsant effects (Joy et
al., 1984; Loscher and Schwark, 1985; Shin et al., 1986).
However, little is known about the role of the GABAer-
gic system in epileptogenesis. Reduction or blockade of
inhibitory transmission produces epileptiform discharges,
and, if repeated, it can induce epileptogenesis. Thus,
repeated intra-amygdala applications of the GABAAreceptor
antagonist picrotoxin (Cain, 1987) or bicuculline (Uemura
and Kimura, 1988) produces a kindling-like effect. On the
other hand, enhancing GABAergic inhibition can prevent or
retard epileptogenesis. Thus, in SE animal models, pretreat-
Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy 109
ment with GABA agonists can prevent the development of SE
and the ensuing brain damage and epileptogenesis (Inoue et
al., 1992; Morimoto et al., 2004). In addition, GABAAago-
nists retard kindling induced by electrical stimulation of the
amygdala (Joy et al., 1984; Shin et al., 1986; Schwark and
Haluska, 1987). These studies suggest that the GABAergic
system can control the induction of epileptogenesis.
After epileptogenesis has been induced, does impaired
GABAergic inhibition play a role in the progression of
epileptogenesis? In humans, certain idiopathic epilepsies
are associated with mutations affecting GABAA receptors
(Lerche et al., 2005), which would suggest a causative or
contributing role of impaired inhibition in the development
of epilepsy. In addition, it is well-established, at least in
animal models, that GABAergic neurons can suffer severe
damage after an acute brain insult that triggers epileptoge-
nesis (see next paragraph; Tuunanen et al., 1996; Pitkanen
et al., 1998). Does the damage of GABAergic neurons play a
major role in the progress of epileptogenesis? When GABA
agonists are administered after the acute insult they do
not prevent epileptogenesis (Andre et al., 2001; Halonen
et al., 2001; see also reviews by Loscher, 2002; Morimoto
et al., 2004). For example, following SE induced by amyg-
dala stimulation, subcutaneous administration of vigabatrin
via osmotic minipumps — to produce a chronic elevation of
brain GABA levels — for 10 weeks did not prevent the devel-
opment of spontaneous seizures or pathology (Halonen et
al., 2001). This suggests that the development of sponta-
However, alterations in inhibition do occur during epilep-
togenesis as suggested by the pathophysiology of neuronal
circuits when epilepsy has developed. GABAergic synaptic
transmission is impaired in epilepsy, although the nature
and the extent of the impairment differ depending on brain
region, methods used to induce epilepsy in animal models,
and time elapsed from the point of time the initial insult
occurred (Treiman, 2001; Morimoto et al., 2004).
In the lateral amygdala of TLE patients, Yilmazer-Hanke
et al. (2006) have reported a reduction in the number of
axosomatic inhibitory synaptic profiles at the somata of
GAD-negative projection neurons, and the magnitude of the
reduction correlated with the extent of perisomatic fibril-
lary gliosis. In animal models, amygdala-kindled rats, at 2—6
months after experiencing three to five generalized seizures
(in addition to the seizures that occurred during the induc-
tion of kindling) had a 37—64% loss of GABA-immunoreactive
neurons in the basolateral amygdala (Callahan et al., 1991).
Others have found that the amygdala interneurons that are
most susceptible to damage by seizure activity are the
somatostatin-immunoreactive neurons in the medial divi-
sion of the lateral nucleus and the magnocellular division of
the basal nucleus of the amygdala (Tuunanen et al., 1996;
Pitkanen et al., 1998). Almost all somatostatin-containing
axon terminals in the BLA form symmetrical synapses, the
vast majority of which target distal dendrites of pyrami-
dal cells (Muller et al., 2007); this suggests that the loss
of somatostatin-containing neurons may have a significant
impact on the excitability of the BLA circuitry. When epilep-
togenesis is triggered by kainic acid-induced SE, there is a
44% loss of GABAergic neurons in the lateral nucleus, and
75% loss in the basal nucleus, at 2 weeks after SE (Tuunanen
et al., 1996).
Some information is also available on the functional
impact of the damage and/or loss of GABAergic neurons
on GABAergic synaptic inhibition in the epileptic amyg-
dala. Thus, in BLA neurons from amygdala-kindled rats,
IPSPs elicited by direct electrical stimulation of interneu-
rons are not altered (Rainnie et al., 1992; Shoji et
al., 1998). However, there is a significant reduction in
feedforward GABAergic synaptic inhibition and in sponta-
neous IPSPs (Rainnie et al., 1992), suggesting interneuronal
loss and/or impairment in the excitation of interneurons.
In lateral amygdala neurons of rats becoming epilep-
tic after pilocarpine-induced SE, the peak conductance
of both fast (GABAA receptor-mediated) and late (GABAB
receptor-mediated) components of the IPSPs is reduced, the
reversal potential of GABAAreceptor-mediated IPSPs is more
depolarized (increasing the likelihood that GABAAreceptor-
mediated synaptic transmission will have a depolarizing
postsynaptic effect), the frequency of spontaneous IPSPs is
reduced, and the efficacy of presynaptic GABAB receptors
in inhibiting GABA release during repetitive activation of
GABAergic synapses also appears reduced (Benini and Avoli,
2006). In the basolateral amygdala of rats becoming epilep-
tic after kainic acid-induced SE, enhanced excitability and
responsiveness is in part attributable to impaired inhibition
(Smith and Dudek, 1997). In the basal amygdala from epilep-
tic rats, after SE induced by hippocampal stimulation, fast
inhibitory potentials had a more rapid onset and shorter
duration than control or kindled rats, while no spontaneous
inhibitory potentials were observed in neurons from either
epileptic or kindled rats (Mangan et al., 2000). It appears
therefore that in addition to interneuronal loss, which can
be present in both the kindling and the SE animal models
but is more extensive in the latter, presynaptic and postsy-
naptic alterations in GABAergic synaptic transmission have
been found in the SE models.
Summary and concluding remarks
It is clearly evident from the existing literature that the
amygdala plays a central role in the pathogenesis and symp-
tomatology of TLE. The relative importance of the amygdala
in the pathogenesis of TLE differs among TLE patients,
which, to a significant extent, is probably due to the vary-
ing etiologies of TLE. When amygdala pathology is part of
the diagnostic profile, the nature of the pathology is atro-
phy, associated with neuronal loss and gliosis. Consistent
among species (humans included) is that the pathological
alterations occur for the most part within the lateral and
basal amygdala nuclei, which are also the nuclei that are
most prone to seizure generation, and provide the output
pathways that spread seizure activity from the amygdala to
other brain regions. Studies in animal models where epilepsy
is induced by an acute brain insult have suggested that the
pattern of neuronal loss (regions that suffer the most dam-
age and types of neurons that are most sensitive) in the
lateral and basal nuclei is such that seizure activity from the
atrophied, epileptic amygdala can still easily spread to other
brain regions. To what extent the severity and the nature of
the initial amygdala pathology, after an acute brain insult,
110 V. Aroniadou-Anderjaska et al.
determines whether or not epileptogenesis will be induced
is not yet clear. It is also unclear to what extent the sever-
ity of the overall amygdala pathology correlates with the
severity of epilepsy. It should be considered, however, that
regardless of the degree of correlation and the cause-effect
relationship between pathology and epileptic seizures, the
presence of amygdala pathology in TLE is also important
as it relates to the emotional and, in part, the cognitive
impairments associated with epilepsy.
Induction of epileptogenesis
Excessive activation of glutamate receptors appears to be
the mechanism by which epileptogenesis is induced in the
amygdala, regardless of whether enhanced glutamatergic
activity is produced directly (e.g. electrical stimulation in
kindling or kainic acid in SE) or indirectly (e.g. repeated
disinhibition, pilocarpine). Which of the glutamate receptor
subtypes are necessary to be activated, which are sufficient,
and which are both necessary and sufficient for epileptogen-
esis to be induced is not yet clear. Their relative contribution
to the induction of epileptogenesis may differ in different
types of brain insults and different experimental models.
However, the evidence so far suggests that NMDA recep-
tors play a pivotal role in triggering epileptogenesis in the
amygdala, as in other brain regions.
The process of epileptogenesis
The cellular alterations that take place in the amygdala
during the process of epileptogenesis are largely unknown.
Despite the fact that enhanced glutamatergic activity and
impaired GABAergic inhibition characterize the epileptic
amygdala, a gradually failing inhibitory transmission or a
progressively enhanced glutamatergic transmission do not
appear to be necessary for epileptogenesis to proceed. It
is also notable that the severity of the early pathologi-
cal damage associated with edema in the amygdala, after
an acute brain insult, is not a good predictor of the out-
come of epileptogenesis, that is, the extent of long-term
pathological alterations and the severity of spontaneous,
recurrent seizures. In attempting to unravel the mechanisms
of epileptogenesis, it should be considered that as there are
differences in the manifestation of epilepsy among patients
and experimental animal models, there may also be differ-
ences in epileptogenesis, not only in time-course, but also
in the nature of the alterations and/or their relative con-
tribution to the development of epilepsy. Such differences
may depend on brain region, as well as on other factors,
most importantly the type of insult that triggers (initiates)
The GABAergic system in the epileptic amygdala
When epilepsy has developed in the amygdala, impaired
GABAergic inhibition appears to be primarily due to
interneuronal loss. However, in SE animal models there
are also presynaptic and postsynaptic changes in GABAergic
synaptic transmission between surviving neurons; the mech-
transmission need to be elucidated. There is also evidence
suggesting that different types of GABAergic interneurons
in the amygdala may have different susceptibilities to
seizure-induced damage, as somatostatin-containing neu-
rons appear to be most sensitive. What makes certain
types of interneurons more vulnerable to seizures, and
what the implications of such differential sensitivities are
on the excitability of the amygdala circuitry remain to
be determined. It is known that GABAergic neurons in
the amygdala contain calcium-binding proteins (McDonald
and Mascagni, 2001), and somatostatin-containing neu-
rons exhibit calbindin- but no parvalbumin or calretinin
immunoreactivity (McDonald and Mascagni, 2002). However,
although it is believed that these proteins play a significant
role in calcium buffering, their relative contribution to cal-
cium homeostasis during epileptic seizures is unclear, and
therefore inferences regarding cell vulnerability to seizures
depending on the type of calcium-binding proteins present
in the cell cannot be made at present. Whether excita-
tion of surviving GABAergic neurons is also altered and how
these alterations compare to those of the excitation of glu-
tamatergic neurons, or how GABAAreceptors are regulated
in the epileptic amygdala are some more of the questions
that have been examined in other brain regions (see for
example Gavrilovici et al., 2006; Qi et al., 2006) but are
presently unanswered in the amygdala.
The glutamatergic system in the epileptic amygdala
Glutamatergic transmission is also altered in the epileptic
amygdala, and this is not only a consequence of impaired
inhibition. Increases in spontaneous glutamatergic activity
and evoked AMPA and NMDA receptor-mediated synaptic
responses have been observed, as well as enhanced, bursting
firing in response to stimulation of afferent inputs, with-
out significant changes in the intrinsic neuronal properties.
More research is needed to delineate the mechanisms of
the enhancement in glutamatergic synaptic transmission;
at present, presynaptic alterations appear to be primarily
involved (Shoji et al., 1998). Because the amygdala is one
of the few brain structures that are rich in GluR5-containing
kainate receptors, and because these receptors have been
shown to play a central role in both the induction and
expression of limbic seizures, the role of these receptors
in epileptogenesis and epilepsy in the amygdala should be
This review has focused primarily on the literature pertain-
ing alterations in glutamatergic and GABAergic transmission
in the amygdala, associated with epileptogenesis and
epilepsy. However, other alterations in the epileptic amyg-
dala, such as those involving ion channels or neurotrophic
factors, can also contribute significantly to hyperexcitabil-
ity, or may counteract hyperexcitability. For example, the
KCNQ2 subunit of potassium channels is upregulated in
the basolateral amygdala in amygdala-kindled rats and
in spontaneously epileptic rats after SE induced by hip-
pocampal electrical stimulation (Penschuck et al., 2005);
since potassium channels containing the KCNQ2 subunit
Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy 111
serve to stabilize membrane potential, the upregulation of
the KCNQ2 subunit could be an important compensatory
mechanism to counteract hyperexcitability (Penschuck et
al., 2005). In addition, the brain-derived neurotrophic fac-
tor (BDNF) can have both epileptogenic and antiepileptic
effects (Koyama and Ikegaya, 2005), and the antiepileptic
effects appear to be mediated via neuropeptide Y (Reibel et
al., 2000, 2003; Koyama and Ikegaya, 2005). The amygdala,
and the BLA in particular, is rich in neuropeptide Y and its
receptors (Stani´ c et al., 2006; Oberto et al., 2007), which
are upregulated by seizure activity (Lurton and Cavalheiro,
1997; Vezzani and Sperk, 2004). It is therefore important to
the excitability of the amygdala, and exploit it for the pre-
vention of epileptogenesis and the treatment of epilepsy.
Finally, it should be noted that pathological and functional
alterations in glia cells in the amygdala, and their impact
on epileptogenesis and epilepsy is still a largely unexplored
The recent development of two strains of rats with differ-
ent susceptibilities to kindling and particularly to amygdala
kindling (Racine et al., 1999; McIntyre et al., 1999) can
provide invaluable insights into the mechanisms underly-
ing predisposition to epilepsy, particularly in relation to
these mechanisms in the amygdala. A number of differences
have already been found between the kindling-prone and
kindling-resistant rats, which include differences in their
susceptibility to induction of SE by kainic acid and the
nature of the resulting pathology (Xu et al., 2004; Gilby
et al., 2005), the amino acid and monoamine neurotrans-
mitter release in the amygdala during intense amygdala
stimulation (Shin et al., 2004), GABAergic function in limbic
structures (McIntyre et al., 2002), as well as noradrener-
gic function (Gilby et al., 2005; Shin and McIntyre, 2007).
In regard to the noradrenergic function, it is particularly
interesting that after kainic acid-induced SE, the kindling-
prone rats showed a reduction in alpha1 adrenoceptor mRNA
in the hippocampus and the amygdala, whereas an increase
was observed in the slow-kindling rats (Gilby et al., 2005).
Alpha1 adrenoceptors are involved in anxiety disorders and
depression (Brunello et al., 2003; Taylor et al., 2006), the
role of the alpha1A adrenoceptor subtype in the BLA is
facilitation of GABAergic transmission (Braga et al., 2004b),
and the function of alpha 1A adrenoceptors in the BLA
is significantly impaired by stress (Braga et al., 2004b;
Aroniadou-Anderjaska et al., 2007), which is, at least in
part, due to reduction in alpha1A mRNA (Braga et al., unpub-
lished). These findings point to the commonalities between
epilepsy and certain emotional disorders in regard to the
derangements in the regulation of neuronal excitability in
the amygdala, and suggest that unraveling the mechanisms
regulating neuronal excitability in the amygdala will facil-
itate progress in the prevention and treatment of both
epilepsy and a host of affective disorders.
We thank Drs. Sean Manion and Dmitriy Fayuk for stimulating
discussions. This work was supported by the Uniformed Ser-
vices University of the Health Sciences Grant H070SG and
by the National Institutes of Health CounterACT Program
through the National Institute of Neurological Disorders and
Stroke (award # U01 NS058162-01). Its contents are solely
the responsibility of the authors and do not necessarily rep-
resent the official views of the federal government. This
work was also supported by the Defense Threat Reduction
Agency grant # 1.E0021 07 US C.
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