A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat
Introduction
There are more than 100 seizure models currently available for epilepsy research (for review, see Fischer, 1989, Löscher, 1997). Seizures occur spontaneously in only a few of them. These models include the systemic or intracerebral injection of kainic acid (Chronin and Dudek, 1988, Mathern et al., 1993, Mascott et al., 1994, Hellier et al., 1998), systemic injection of pilocarpine (Priel et al., 1996), and electrical stimulation of the ventral hippocampus (Lothman et al., 1989, Bertram and Cornett, 1993, Mathern et al., 1997) or the angular bundle (Shirasaka and Wasterlain, 1994, Halonen et al., 1996). In these models, the induction of epileptogenesis is dependent on the occurrence and duration of self-sustained status epilepticus (SSSE). Electrographic seizures have also been described after brain ischemia (Rominj et al., 1994), cortical trauma (Prince and Jacobs, 1998), or after a large number of kindling stimuli (Hiyoshi et al., 1993).
There are multiple advantages of epilepsy models with spontaneous seizures. For example, in models of temporal lobe epilepsy (TLE) all phases of the epileptic process that are typical to human symptomatic TLE (initial insult→epileptogenesis→generation of spontaneous seizures) can be investigated. Also, many pathologic findings in spontaneously-seizing animals resemble the appearance of structural damage in human drug-refractory symptomatic TLE (Liu et al., 1994). The few details known regarding the seizure symptomatology in these models suggests that spontaneous limbic seizures in rats are broadly similar to those in human TLE (Bertram, 1997). Finally, a study using the pilocarpine epilepsy model indicates that the effect of antiepileptic drugs on spontaneous seizures predicts their effect on seizures in patients with TLE (Leite and Cavalheiro, 1995).
Recently, it has become evident that the period after epileptogenic insult such as status epilepticus is not ‘silent’ but includes, for example, activation of over 1000 genes (Nedivi et al., 1993, Rafiki et al., 1998), acute and delayed neuronal damage (Magloczky and Freund, 1995, Fujikawa et al., 1998), and axonal (Mello et al., 1993) and dendritic (Spigelman et al., 1998) plasticity. There is a growing interest in the molecular and network changes associated with various initial insults and consequent epileptogenesis (Morrell and DeToledo-Morrell, 1999, Salazar and Ellenbogen, 1999). This interest has been further fueled by the challenging goal of preventing epilepsy in subjects that are at elevated risk of developing epilepsy later in life after brain insults, such as status epilepticus, head trauma, stroke, prolonged complex febrile seizures, or brain infection (Hernandez and Naritoku, 1997, Pitkänen and Halonen, 1998). Achievement of these goals, however, will require appropriate modeling of different phases of the human epileptic process.
With the exception of genetic models, and the recently described perforant pathway stimulation model (Mazarati et al., 1998), the induction of SSSE includes an injection of a chemoconvulsant, or a long-lasting (>1 h) or repeated electrical stimulation. The principal aim of the present study was to induce epileptogenesis culminating in spontaneous seizures by using a local manipulation of the brain that is nontoxic and is as short-lasting as possible. Here, we describe a new model of human TLE, in which epileptogenesis is induced by electrically stimulating the lateral nucleus of the amygdala for 20–30 min. After a latency period of approximately 1 month, animals express spontaneous seizures that continue to occur for the rest of the animals life. The occurrence of spontaneous seizures was followed by continuous video-EEG monitoring system for 6 months. The results of the present study indicate that the symptomatology of spontaneous seizures, neuropathology, and behavioral impairment of these epileptic animals closely resembles that found in human TLE. Thus, this model provides a useful and novel tool with which to better investigate the mechanisms of status epilepticus, epileptogenesis, and spontaneous seizures, as well as their prevention.
Section snippets
Animals
Adult male Harlan Sprague–Dawley rats (n=28; 320–390 g) were used in this study. The rats were housed in individual cages in a controlled environment (constant temperature, 22±1°C, humidity 50–60%, lights on 07:00–19:00 h). Animals had free access to food and water. All animal procedures were conducted in accordance with the guidelines by the European Community Council Directives 86/609/EEC.
Implantation of stimulation and cortical EEG electrodes
For amygdala stimulation, a bipolar electrode (diameter 0.127 mm, dorsoventral distance between the tips
Results
A total of 28 rats were included in the study: eight unstimulated controls with electrodes implanted in the amygdala and 20 stimulated animals. Four of the 20 stimulated rats died within 24–48 h after the induction of status epilepticus. In one of the stimulated animals, the stimulation electrode was located outside the amygdala, and therefore, the rat was excluded from the final analysis.
Discussion
The aim of the present study was to develop an epilepsy model in which the epileptogenesis and appearance of spontaneous seizures is similar to that in human symptomatic TLE. That is, the initial insult is followed by a latency period, and thereafter, by spontaneous seizures. In the induction of SSSE, we wanted to avoid chemical substances with possible direct toxic effects on neurons. Another goal was to minimize the length of electrical stimulation to avoid structural damage caused by the
Conclusions
Like the development of symptomatic TLE in humans, the epileptogenic process in our model has three major phases that succeed each other sequentially: initial insult→latency period or epileptogenesis→epilepsy. There are several other similarities between the present model and human symptomatic TLE: (1) the occurrence of spontaneous seizures after a latency period; (2) behavioral appearance, duration, frequency and diurnal distribution of seizures; (3) distribution and appearance of temporal
Acknowledgements
We thank Merja Lukkari for her excellent technical assistance.
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