Animal Models for Epilepsies 2221 Focal Epilepsy Models

An important early work to elucidate the neuronal disturbances underlying ictal discharge, and interictal electroencephalogram (EEG) spikes, used the acute cat neocortical penicillin focus (Matsumoto and Ajmone-Marsan 1964). In vivo extracellular recording within the experimental epileptic focus revealed normally firing neurons, except for abnormal burst discharges during the EEG spike, and cessation of firing during the aftercoming slow wave. Intracellular recordings demonstrated that the bursting was caused by membrane depolarization of unusually high amplitude and prolonged duration, which was called a paroxysmal depolarization shift (Matsumoto and Ajmone-Marsan 1964). This was followed by a prolonged high amplitude after hyperpolarization during which normal action potentials were inhibited. In most cases, the paroxysmal depolarization shift appeared to reflect an abnormal Ca2+ current of dentrites and soma, associated with continuous Na+ action potentials at the axon hillock for as long as the depolarization persisted. A high percentage of neurons within the experimental epileptic focus participated synchronously in these transient events, producing the negative EEG deflection characteristic of the interictal spike. It could be concluded that ictal onset in the penicillin focus model appears to be due to dysinhibition.

Subsequent in vivo studies on patients with mesial temporal lobe epilepsy, using depth electrodes, including microelectrodes, revealed that only 5% of the recorded neurons in humans demonstrate this behavior (Babb et al. 1973), compared with over 90% in the experimental penicillin focus (Matsumoto and Ajmone-Marsan 1964). Consequently, synchrony in bursting neurons is difficult to demonstrate in patients. Furthermore, the EEG pattern of ictal onset in the human epileptogenic hippocampus typically does not consist of recruiting rhythm but rather pronounced repetitive high amplitude spike wave discharges (Velasco et al. 2000), sometimes resembling the EEG pattern of absence seizures, where the prominent slow wave represents enhanced inhibition (Giaretta et al. 1987).

The kindling model may approximate the human condition more closely than directly evoked seizure models. Since its discovery by Goddard et al. (1969), the kindling phenomenon has been used as a chronic animal model of TLE. In limbic kindling, low-intensity electrical stimulation of certain regions of the limbic system, such as the amygdala, with implanted electrodes normally produces no seizure response. If a brief period of stimulation is repeated daily for several days, the response gradually increases until very low levels of stimulation will evoke a full seizure and eventually seizures begin to occur spontaneously (Goddard et al. 1969). Once produced, the kindled state persists indefinitely. Kindling is still widely accepted as a functional model in which the altered neuronal response develops in the absence of gross morphological damage, such as that seen in many other epilepsy models. High doses of neurotoxins such as kainate or pilocarpine are administered systematically to produce status epilepticus (continual recurrent seizures). In that case, it is not the status epilepticus that is of interest, but the delayed appearance of spontaneous seizures. Thus, this model has been named "post-status epilepticus models of TLE" (Morimoto et al. 2004). Unilateral lesions more similar to unilateral human mesial temporal lobe epilepsy can be produced with intrahippocampal injections of kainic acid (Bragin et al. 1999). After transient intense stimulation, spontaneous seizures begin to occur 2-4 weeks later, and again continue indefinitely. The hippocampal lesions in all of these models consist of the same cell loss, axon sprouting, synaptic reorganization, and gliosis seen in human hippocampal sclerosis with mesial temporal lobe epilepsy, but the maximal cell loss in patients is in the CA1 region and in the CA3 region in rats. Dube et al. (2006) directly address the causal relationship of long febrile seizures and development of TLE. Focal neocortical epilepsy has been modeled using topical application of toxic metals such as cobalt, aluminium, and iron (Ward 1972). These lesions produce focal seizures for prolonged periods of time and may mimic human focal epilepsies due to scars and hemosiderin deposits caused by trauma, stroke, and vascular malformations.

Kharatishvili and coworkers studied the electrophysiological, behavioral, and structural features of posttraumatic epilepsy induced by severe, nonpenetrating lateral fluid-percussion brain injury in rats (D'Ambrosio et al. 2005; Kharatishvili et al. 2006).

There is also evidence that neurotrophins, particularly brain-derived neurotrophic factor (BDNF), may play a role in epileptogenesis. Brain-derived neurotrophic factor, which acts on a membrane receptor tyrosine kinase, enhances membrane excitability and also stimulates synapse formation. Production and release of BDNF is increased in the kindling models, and there is also evidence for its involvement in human epilepsy. Models of focal epilepsies are summarized in Table 22.1.

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