C H A P T E R
30
Electrical Kindling in Developing Rats
ARISTEA S. GALANOPOULOU AND SOLOMON L. MOSHÉ
METHODS OF GENERATION
Animal Issues
Because of the rapid growth of infant rats, kindling stim-
ulations must be delivered within a finite period of time,
usually 48 hours. The first protocol of amygdala kindling in
infantile rats (P15–18) was published by Moshé in 1981
using 1 hour interstimulus intervals (ISI) with 60 Hz alter-
nating current stimulations. However, even shorter (15
minute) ISI were able to effect successful kindling, due to
the lack of a refractory period (Moshé, 1981; Moshé et al.,
1981; Moshé and Albala, 1983; Haas et al., 1990). With
this paradigm, kindling can occur within 1 day. This is
not the case with adult rats. Irrespective of the ISI, kindling
once induced is permanent and persists into adulthood
either in the original kindling site or the contralateral site
(Moshé and Albala, 1982). Subsequently, several other
studies adopted the 15 minute ISI kindling protocol and
succeeded in kindling rats as young as P7 (Baram et al.,
1993; Baram et al., 1998), and covering all the stages
of development, i.e., the infantile (P8–P20), juvenile
(P21–P34), and pubertal period (P35–P40) (Dahl et al.,
1988; Ojeda et al., 1986). These studies revealed several
age-related differences in kindling parameters, expression,
and consequences. Briefly, age-related differences have been
found in the presence of a refractory period, the after-
discharge (AD) threshold (ADT), kindling rate, behavioral
manifestations of kindled seizures, the interaction between
2 foci kindled concurrently, and neuropathologic and meta-
bolic sequelae.
Models of Seizures and Epilepsy
Procedures
Electrode Implantation
Electrode implantation is done at least 1 day prior to
kindling in P7–8 Sprague-Dawley rats (Baram et al., 1993;
Baram et al., 1998) and 2 days prior to testing in P9 or older
rats (Baram et al., 1993; Baram et al., 1998; Moshé, 1981;
Moshé et al., 1981). The recovery period needs to be shorter
in infant rats than in adults, to avoid misplacement of the
electrode tip due to the ongoing head growth.
P6–10 rats are anesthetized under halothane anesthesia
(Baram et al., 1993; Baram et al., 1998), whereas P12 or
older rats are injected with a mixture of ketamine (70 mg/kg
IP) and xylazine (6 mg/kg IP) (Moshé 1981; Moshé et al.,
1981). When deeply anesthetized, rats are placed on an infan-
tile rat stereotaxic apparatus. The tooth bar is set at 3.5 mm.
Bipolar twisted wire electrodes are targeted through a burr
hole, to the basolateral nucleus of the amygdala unilaterally.
In P6–10 pups, bipolar electrodes with a wire diameter of
0.1–0.15 mm and vertical inter-tip distance of 0.5–1 mm have
been used (Baram et al., 1993; Baram et al., 1998). In older
pups, insulated electrode with wire diameters 0.23–0.35 mm
(MS 303/1 or MS 303/2, Plastic One, Roanoke, VA, USA)
can be used (Moshé 1981; Haas et al., 1998). The coordinates
used to target each structure are based on the stereotaxic
coordinates included in the atlas by Paxinos (Paxinos et al.,
1994; Paxinos and Watson, 1997) but they need to be
adjusted according to the age, strain, source, or weight of the
rats. Table 1 presents published coordinates that can be used
as starting points when targeting the amygdala or other sites.
Copyright © 2006, Elsevier Inc.
371 All rights of reproduction in any form reserved.
372 Chapter 30/Electrical Kindling in Developing Rats

In this lab, electrodes are usually inserted at a 0° angle in ref-
erence to the vertical plane (Table 1A). If additional elec-
trodes or cannulae need to be inserted, the electrodes can be
placed at a different angle, with appropriate adjustment of the
coordinates (Table 1B).
Electrodes are then fixed to the skull with 2 or 3 screws
and dental acrylic. The pups are then returned to the litter.
We prefer to keep the mother separated from the infants till
all the pups are operated. We then cover the pups with the
shavings already present in the cage to cover up any obnox-
ious smells acquired during the procedure. When pups are
ready to kindle, they are placed in a test box and are con-
nected to the stimulating and recording apparatus via a con-
nector cable (Plastics One; MS 303 series). Recording of the
EEG is done before and after each stimulation.
Kindling
The first step is to determine the ADT. A 60 Hz sinusoidal
current is delivered for 1 second. Stimulations can be deliv-
ered as frequently as every 2 minutes, until an AD is elicited.
Once an AD is observed, the ISI is kept at 15 minutes or as
otherwise stated in the selected protocol (Table 2).
If determination of ADT is an endpoint in the experi-
mental design, a protocol using small increments of stimu-
lation amplitude may be used. For example, stimulations can
be started at 30 mA and increased by 30 mA in each subse-
quent trial until an AD is obtained (Moshé et al., 1981). The
current can then be decreased by 15 mA. If an AD is evoked,
the current can further be increased by 5 mA increments until
the lowest current that can generate an AD is reached
(Moshé et al., 1981).
In most cases, however, ADT determination simply
serves the purpose of ensuring that all subsequent stimula-
tions will be above ADT to achieve successful kindling.
In such cases, the starting stimulus intensity can be set at
100 mA and progressive increments by 100 mA are applied
till an AD is recorded. Generally, rats not responding to
500 mA stimulation with an AD are excluded, as they have
been shown to be refractory to kindling (Moshé SL, unpub-
lished data). Determination of the ADT is done the same day
as kindling.

TABLE 1 Age- and Site-Specific Coordinates for Targeting Limbic Structures for Kindling

A. Insertion at 00 angle

Antero-posterior in
Age (days) Tooth bar (mm) reference to bregma (mm) Lateral (mm) Depth (mm) Reference

Basolateral nucleus of the amygdala

7–14 -3.5 -1.5 to -1.8 3.5 6.5–7.4 (Moshé, 1981)
≥32 -3.5 -1.5 3.5 8.8 (Moshé, 1981)
Dorsal hippocampus
13–14 -3.5 -3.2 2.7 to 3 2.8–3 (Haas et al., 1990)
Ventral hippocampus
7–21 0 -3 to -2.9 3.7–4.9 3.7–4.9 (Michelson and
28 5 -3.6 4.9 4.9 Lothman, 1991)
Deep endopiriform cortex
13 -3.5 -1.2 3.1 5.5 (Sperber et al., 1998)
Piriform cortex
13 -3.7 -1.2 3.7 6 (Sperber et al., 1998)

B. Angled coordinates

Antero-posterior
in reference to
Age (days) Tooth bar (mm) Angle bregma (mm) Lateral (mm) Depth (mm) Reference

Basolateral nucleus of the amygdala

14 -3.5 150 forward +5 3.5 7.4 (Haas et al., 1992)
Dorsal hippocampus
13–14 -3.5 150 backward -4 3 2.9 (Haas et al., 1992)

Stereotaxic coordinates for targeting the basolateral nucleus of the amygdala, the dorsal or ventral hippocampus, the deep endopiriform cortex, and the
piriform cortex in developing Sprague-Dawley rats. Insertion is routinely made at a 00 angle, in reference to the vertical plane (Table 1A). If additional
electrodes need to be placed, angled coordinates can be used (Table 1B). Further adjustments may need to be made according to the specific strain, source,
or weight of the rats.
 Methods of Generation 373

TABLE 2 Age and Site-Specific Protocols of Kindling in Developing Rats

Site Age Protocol Reference

Amygdala (basolateral P7–12 1 sec pulse, 60 Hz monophasic current, 400 mA, 15 min ISI (Baram et al., 1993)
nucleus) P15–18 1 sec pulse, 60 Hz sinusoidal current, 400 mA, 15 min ISI (Moshé et al., 1983)
1st day: 20 stimulations; 2nd day: 10 stimulations
P30–35 1 sec pulse, 60 Hz sinusoidal current, 400 mA, 60 min ISI (Moshé, 1981) (Moshé et al., 1981)
1st day: 20 stimulations; 2nd day: 10 stimulations (Holmes and Weber, 1983)
Deep endopiriform P15–16 1 sec pulse, 60 Hz sinusoidal current, 400 mA, 15 min ISI, (Sperber et al., 1998)
nucleus 1st day: 20 stimulations; 2nd day: 10 stimulations
Piriform cortex P15–16 1 sec pulse, 60 Hz sinusoidal current, 400 mA, 15 min ISI, (Sperber et al., 1998)
1st day: 20 stimulations; 2nd day: 10 stimulations
Dorsal hippocampus P15–17 1-sec, 400 mA. 60 Hz, sinusoidal current, every 15 min (Haas et al., 1992)
1st day: 20 stimulations; 2nd day: 10 stimulations
P30 10-sec, 10 Hz or 60 Hz, 1000 mA, 5 min ISI (Holmes and Thompson, 1987)
Ventral hippocampus P7–28 10-sec, 20 Hz, every 30 min for 9 hours per day, 2 days (Michelson and Lothman, 1991)
Perforant pathway P14–60 10-sec, 60 Hz, bipolar square wave pulses, twice the ADT, (Trommer et al., 1994)
every 30 min

When the ADT is determined, the amplitude of the stim-
ulation current used for kindling can be set at 100 mA higher
than the ADT and kept the same throughout the kindling pro-
tocol. In most protocols, however, amplitude can be set at
400 mA, which is sufficient to kindle rats at all ages and in
most sites. To kindle the amygdala, stimulations (1 second,
60 Hz sinusoidal, 400 mA) are delivered every 15–20
minutes, to a maximum of 20 stimulations the first day. Kin-
dling continues until pups develop three consecutive bilat-
eral/generalized seizures (i.e., stage 3.5 to stage 7; Table 3).
A measure of how fast kindling proceeds is the kindling rate,
i.e., the number of stimulations required to achieve the first
of three consecutive bilateral seizures (stage 3.5 to stage 7,
Table 3). Between stimulations, pups are returned to their
dam. After 10 stimulations, pups are rested for 1 hour before
resuming kindling. The following day, pups are again
kindled up to 10 times, or until they develop three consec-
utive stage 3.5–7 seizures. A total of 30 stimulations over a
2-day period can elicit stage 6 or 7 repeated seizures, which
last for 100–120 seconds (Sperber et al., 1992).
Postictal refractoriness can be measured an hour after the
last kindled seizure, delivering eight repetitive 1-second
stimulations, 400 mA, 60 Hz pulses, every 2 minutes, and
comparing the AD duration and the kindling stage (Moshé
and Albala, 1983).
When kindling permanence or the long-term effects of
kindling are studied, it is necessary to remove the original
electrodes to avoid misplacement of the tip due to continu-
ing head growth as well as infectious/inflammatory compli-
cations. New electrodes may then be re-inserted at a later
stage if needed in the experimental design (Moshé and
Albala, 1982).
The sensitivity of different brain regions to kindling is,
however, different. Attempts to kindle the dorsal hippocam-
TABLE 3 Behavioral Manifestations of Kindling
in Infantile Rats
Stage Behavior
0 Behavioral arrest
1 Mouth clonus
2 Head bobbing
3 Unilateral forelimb clonus
3.5 Alternating forelimb clonus
4 Bilateral forelimb clonus
5 Bilateral forelimb clonus with rearing and falling
6 Wild running and jumping with vocalizations
7 Tonus
The currently used seizure scales describing the progression of
seizures during kindling of infantile pups are based on the modified
infantile scale initially proposed by Moshé (Haas et al., 1990; Haas et al.,
1998). Age- and site-related variations may be observed as discussed in
section IIA. (Reproduced from Haas et al., 1990, with permission from
Elsevier.)
pus, piriform cortex, deep endopiriform nucleus (“area tem-
pestas”) and amygdala in P15–17 pups, using the same
experimental protocol, showed that the deep endopiriform
nucleus kindled the fastest (Sperber et al., 1998; Haas et al.,
1998). The different sensitivity to kindling in certain cases
necessitated the use of site-specific protocols, as summa-
rized in Table 2. Modifications may thus need to be made in
the duration and frequency of the stimulation as well as the
ISI. In the study by Michelson and Lothman, kindling of
the ventral hippocampus of P7–28 rats with 5 minute-ISI
resulted in erratic kindling, whereas efficiency was im-
proved with ISIs of 30 minutes (Michelson and Lothman,
374 Chapter 30/Electrical Kindling in Developing Rats
1991). These differences may suggest the existence of a
relative refractory period in the ventral hippocampus at this
age.
CHARACTERISTICS AND
DEFINING FEATURES
Monitoring
ADT/Kindling Rates
Age- and site-related differences in ADTs have been
reported. In the amygdala, the highest ADT occurs at
P15–18 and declines thereafter till adulthood (Moshé et al.,
1981). Kindling rate is the lowest at P7–8 rats (Baram et al.,
1998), highest at P35, and intermediate at the other ages
(Moshé et al., 1981). The effects of age on ADTs and
kindling rates may differ in other brain sites (Holmes et al.,
1987; Trommer et al., 1994; Lee et al., 1989; Haas et al.,
1998). For instance, although dorsal hippocampus kindles as
fast as the amygdala and piriform cortex in 2-week-old pups,
in adults hippocampal kindling proceeds at a slower rate
than in the other brain sites (Haas et al., 1998; Lee et al.,
1989; Moshé 1981; Moshé et al., 1981).
Behavioral/Clinical Features
Kindled seizures are semiologically different in infants
than in adults. This prompted the adoption of a modified
seizure scoring scale, based on the seizures observed in
P15–18 rats undergoing amygdala kindling (Table 3) (Haas
et al., 1990). The main differences from the adult scale
include the appearance of alternating forelimb clonus in the
same or consecutive seizures (stage 3.5), which is indicative
of bilateral or generalized seizures. The incomplete myeli-
nation of the corpus callosum has been postulated to be a
reason for the development of asynchronous bilateral motor
manifestations (Haas et al., 1998; Gravel and Hawkes 1990;
Kristensson et al., 1986). Another distinguishing feature of
kindling of the immature rats is the early appearance of
severe kindled seizures. Following the development of stage
5 seizures, P15 rats also develop more severe seizures, con-
sisting of wild running with jumping and vocalizations
(stage 6 seizures) and sometimes tonus (stage 7 seizures)
(Haas et al., 1990). This may occur early on, after only less
than 30 stimulations. In contrast, in adult rats more than 100
stimulations may be required to induce similarly severe
seizures (Haas et al., 1998). The incidence of stage 6 or 7
seizures depends upon the stimulated site. Sixty to 80% of
pups kindled at the amygdala, hippocampus, or area tem-
pestas develop severe seizures, whereas none of those
kindled at the piriform cortex do (Haas et al., 1990; Sperber
et al., 1998). In P7–9 pups, alternating clonus and rearing
were rarely observed (Baram et al., 1993). Furthermore,
P7–9 kindled rats rarely develop bilateral clonic seizures or
rearing and progress from unilateral clonic seizures to tonic
seizures (Baram et al., 1998). The kindled seizures in peripu-
bertal rats are semiologically similar to those observed in
adults, and therefore the adult scale can be used (Racine,
1972) (see also Chapter 28 on “The Kindling Phenomenon”).
Similar scales have also been adopted in studies of kindling
at other sites (Sperber et al., 1998; Haas et al., 1998; Michel-
son and Lothman, 1991; Holmes and Thompson, 1987; Lee
et al., 1989) (Table 3).
P15–17 pups are also more prone to develop recurrent
kindled seizures and status epilepticus than adult rats
(Moshé and Albala, 1983). The absence of a postictal refrac-
tory period in infant rats has been proposed to be a factor
contributing to this increased propensity of the immature
brain to develop status epilepticus or recurrent kindled
seizures (Moshé and Albala, 1983).
Kindling Antagonism
In contrast to adult kindled rats, P15–17 pups do not exhibit
kindling antagonism (Haas et al., 1998). Concurrent kindling
of the amygdala with either the contralateral amygdala or the
contralateral or ipsilateral hippocampus, using alternating
stimulations at each site, accelerated the kindling at each site,
with pups manifesting more severe, and occasional sponta-
neous, seizures (Haas et al., 1998; Haas et al., 1990; Haas et al.,
1992). These findings suggest that the immature brain is not
yet ready to suppress the development of multiple kindling
foci, explaining therefore the higher incidence of multifocal
seizures in the immature brain (Haas et al., 1992).
Spontaneous Seizures
Amygdala kindling may lead to the appearance of spon-
taneous seizures. In the study by Baram’s group, sponta-
neous seizures were defined as those observed at least 4
minutes after the last stimulation and typically after stage
3.5–5 seizures. Spontaneous seizures in that study persisted
for 2–3 hours, till sacrifice. The investigators found that
spontaneous seizures appeared in 25–50% of kindled P7–12
pups (Baram et al., 1998). Spontaneous seizures resembling
stage 6 seizures (wild running, jumping, and vocalizations)
have also been reported in P15–16 pups kindled with
alternating stimuli at the ipsilateral amygdala and dorsal
hippocampus (Haas et al., 1992). There are, however, no
long–term monitoring studies to determine whether and how
long spontaneous seizures continue to occur till adulthood.
Persistence of Kindling
Kindling of limbic structures during the infantile period
appears to leave persistent alterations in the brain, through
adulthood. P15–18 rats kindled to manifest either general-
 Characteristics and Defining Features
ized or focal seizures can be re-kindled faster during adult-
hood, whether stimulation is done at the ipsilateral or con-
tralateral amygdala (Moshé and Albala, 1982; Moshé and
Albala, 1983). For instance, rats that were fully or partially
kindled at P18 required only 3–6 stimulations respectively
to re-kindle in adulthood, as opposed to 10–13 stimulations
needed in controls (Moshé and Albala, 1982). AD duration
was also significantly longer in adult rats that were previ-
ously kindled in infancy and their seizures were more severe
(Moshé and Albala, 1982).
Neuropathology
Histologic examination of kindled rats has not demon-
strated significant histopathologic differences compared to
same-age rats implanted but not kindled (Moshé and Albala,
1983). Nissl staining of brain sections from rats kindled at
P15–17 did not reveal significant cell loss at the CA3c or
CA1 hippocampal regions, 2 weeks following the last
kindled seizure (Haas et al., 2001). Similarly, there was no
significant mossy fiber sprouting in Timm-stained hip-
pocampal sections from these rats (Haas et al., 2001), in
agreement with the studies supporting the relative resistance
of the immature brain to seizure-induced pathologic
changes. These studies demonstrate that kindling in pups is
permanent in the absence of overt histologic changes, albeit
only studied in amygdala and hippocampus.
The development and neuropathologic consequences of
kindling, however, are enhanced in pups that have a pre-exist-
ing neuronal migration disorder. Germano et al. showed that
P15 pups with experimentally-induced neuronal migration
disorder, produced by transplacental injection of methyla-
zoxylmethanol acetate, had lower ADTs, faster kindling rates,
and longer ADs the second day of hippocampal kindling. In
addition, kindled-seizure induced damage was observed at
the CA3 sectors bilaterally (Germano et al., 1998).
Neuroimaging
Increased deoxyglucose uptake in rhinencephalic struc-
tures, but not in basal ganglia or neocortex, was observed
in P15–16 albino rats with stage 6 and 7 kindled seizures
(Ackermann et al., 1989). The increased deoxyglucose
accumulation in the hippocampus was not associated with
concomitant increase in glucose accumulation (Sperber
et al., 1992). It has been proposed that the rapid propagation
and increased severity of seizures at this age may reflect the
immaturity of subcortical structures involved in seizure
control (Haas et al., 1998).
Genetics and Molecular Changes
Kindling has been described mainly in immature
Sprague-Dawley rats (Moshé, 1981; Moshé et al., 1981;
375
Baram et al., 1993; Baram et al., 1998), but also in wean-
ling (3-week old) Wistar pups (Kawahara et al., 1989). It is
the experience of this lab (Moshé SL, unpublished observa-
tions) that the development of kindling in Sprague-Dawley
pups obtained from different sources may vary, suggesting
that exogenous or genetic factors influence this process. The
existence of strain differences in the development of kin-
dling has been well documented in adult Fast and Slow rats,
a crossbreeding of Wistar and Long-Evans rats (Xu et al.,
2004; McIntyre et al., 1999). Similar differences also exist
in immature pups. During amygdala kindling, P15–16 Fast
and Slow rats exhibit an elevated ADT and require longer
ISIs (at least 45 minutes) compared to Sprague-Dawley pups
(Veliskova et al., 2004) . Fast P15–16 pups kindle faster than
Slow pups (Veliskova et al., 2004; Moshé et al., 1981).
There are no studies about the effects of specific genetic
or molecular alterations on the development of kindling or
describing molecular changes resulting from kindling in
developing rats. Furthermore, there are no definitive studies
describing sex differences in kindling in developing rats, as
all of the published data have been obtained from mixed
litters, not analyzed according to sex.
Response to Antiepileptic Drugs/Usefulness
in Screening Drugs
Kindling has been used as a model to test the effects of
a variety of conditions and drugs on the susceptibility of the
developing brain to seizures and the development of the
kindled state. To test whether a drug may alter sensitivity to
kindling, drugs can be administered prior to the first daily
kindling stimulus. It is also possible to study whether a
drug may alter the establishment of the kindled state, by
administering it once the rat is fully kindled. In these stud-
ies, the effects of drugs or pathologic states, such as
hypoxia/ischemia, can be tested in regard to their ability to
alter ADT, kindling rate, AD duration, and seizure severity.
Only few antiepileptic drugs have so far been tested as
to their ability to alter the development of kindling in imma-
ture pups. Diazepam (Albertson et al., 1982) and gabapentin
(Lado et al., 2001) inhibited the development of kindling in
immature rats. Acute and chronic ACTH treatment inhibited
the development of the kindled state (Holmes and Weber,
1986), but had no effect once the kindled state was already
established (Thompson and Holmes, 1987). Furthermore,
other drugs and compounds not included among the con-
ventional antiepileptics have also been tested. For instance,
progesterone-like substances (Holmes and Weber, 1984),
NMDA receptor antagonists (Trommer and Pasternak, 1990;
Holmes et al., 1990), the GABAB receptor agonist baclofen
(Wurpel, 1994), and the calcium channel blockers verapamil
and nimodipine (Wurpel and Iyer, 1994) also inhibited
kindling in developing rats. Estrogens had no effect on the
development of kindling (Schultz-Krohn et al., 1986).
376 Chapter 30/Electrical Kindling in Developing Rats
Baclofen also suppressed the severity and duration of estab-
lished kindled seizures and increased postictal refractoriness
(Wurpel, 1994).
LIMITATIONS
Ease of Development/Reliability
Despite a higher ADT, amygdala kindling is produced
faster in infantile rats compared to adults. The short ISI kin-
dling protocol reliably kindles rats of most ages, although
the success rate may differ according to the specific age and
site. Amygdala kindling of P15–18 rats with 15 minute ISI
kindled 100% of the pups (Moshé et al., 1983). In younger
pups (P7–8) the success of inducing AD with this protocol
falls to 50% (Baram et al., 1993).
Mortality
Mortality during the kindling process is insignificant. If rats
are allowed to grow to adulthood, a higher than expected mor-
tality has been observed in kindled (40%) versus implanted but
not kindled rats (20%) (Moshé and Albala, 1982).
WHAT’S IT GOOD FOR?
Kindling of immature rats has been shown to be a reli-
able method of assessing susceptibility to the development
of seizures and establishing a state of increased seizure sus-
ceptibility that persists till adulthood. Although spontaneous
seizures, the principal feature of the epileptic state, have
been reported, there are no studies documenting the persist-
ence of these spontaneous seizures till adulthood. This may
be due to excessive animal costs and the difficulty of main-
taining intracerebral electrodes in growing animals. There-
fore, kindling in developing rats can probably be used as a
model of epileptogenesis but not as a model of spontaneous
epilepsy. It is a useful method to assess the effect of a variety
of drugs or conditions on several aspects of seizure suscep-
tibility, i.e., ADT, kindling rates, recurrent triggered bilateral
seizures, or postictal refractoriness. Kindling can also be
used to study the consequences of repetitive seizures in the
developing brain and persistence of any seizure-induced
deficits.
Acknowledgements
This work was supported by NIH NINDS grants NS20253 and
NS048856 (SLM), and NS45243 (ASG).
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