Biology Reference
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left largely intact. However, patch clamping and intracellular recordings under these
conditions are much more technically challenging, which promotes the continued use of
methods for in vitro LTP.
Kindling model of epilepsy
Kindling is an experimental model of epilepotogenesis. The term was first proposed by
Goddard et al. who performed many of the early experiments [35]. Kindling has been defined
as a progressive increase in neuronal responsivity generated by spaced and repeated
epileptogenic stimulation in specific brain structures [2, 13, 36-38]. Epileptogenesis has been
defined as a set of progressive neurochemical, neuroanatomical, and neurophysiological
changes that lead to spontaneous recurrent seizures [39, 40].
Controversy has arisen in that kindling may not be an optimal model of epilepsy or
epileptogenesis since kindling does not usually result in a state of spontaneous recurrent
seizures [7]. Instead a low intensity stimulus that normally produces a subtle response will
give rise to seizure discharges (i.e., when a structure is “kindled.”). On the other hand,
kindling does allow a well-controlled experimental examination of the development of
abnormal excitability, which utilizes standard stimulation protocols from animal to animal.
Kindling protocols [19] involve repeated, but intermittent, electrical stimulation or
chemical exposure that eventually results in permanent nervous system change, without gross
tissue damage (at the site of stimulation). The electrical stimulation protocols for kindling
involve some parameters similar to those used for LTP (i.e., 50 to 100 Hz trains). However,
the stimulus trains are typically longer than those used for LTP ( ~
>
1 sec). Further, the
stimulus intensity (often as low as 50-100 μA) is determined by the intensity level of that
producing an AD. Kindling will not occur if the initial stimulus does not produce an AD.
Common sites for stimulation in kindling include the hippocampus and the amygdala, but
a number of other sites have also been used with varying responsiveness [2, 36-38]. The
amygdala, has been reported by many to be the most sensitive to repeated stimulation, but
some studies targeting the olfactory bulb and regions of perirhinal cortex suggest otherwise
and appear to be more sensitive (i.e., produce kindling with fewer trials) than the amygdala.
As a whole, kindling protocols are primarily used as a model of drug-resistant epilepsy and/or
for investigating developmental aspects of epilepsy.
In kindling studies with rats, electrical stimulation in the amygdala is typically repeated
until the animal develops stage-5 convulsive seizures (using the 10 stage classification system
developed by R. J. Racine where stage 10 is the highest [41-43]) or clonic-tonic-clonic
seizures involving all four limbs. Today most common protocols utilize 60 Hz stimulation
trains. Previously, Goddard tried a variety of stimulation frequencies (25, 60, and 150 Hz) and
also found that the animals were maximally sensitive to 60 Hz [35]. Most kindling protocols
use square wave pulse sequences, although a few have used sinusoidal waveforms.
Goddard also initially showed that varying stimulus intensity had little effect on the
number of stimulations required to kindle the amygdala. However, Racine et al. later found
that intensity did make a difference, since epileptiform ADs were required to produce the
neural changes underlying the kindling effect [36]. Although, varying the intensity above
threshold (400 vs. 1000 μA) seemed to make little difference on kindling rate. Goddard et al.
