Generalized Epilepsy and Seizure Models

There are many different animal models of generalized epilepsy (see Table 22.2). Electrical stimulation (maximal electroshock [MES]), chemoconvulsants (kainic acid, pilocarpine, pentylentatrazol, bicucculine, picrotoxin, flurothyl), and genetic models have been used to generate generalized seizures.

Table 22.1 Focal epilepsy models (Modified from Engel 2004; Bagdy et al. 2007; Löscher 2002) Electrical stimulation - acute seizures and chronic (kindling) models

Topical convulsants that block inhibition (penicillin, bicuculline, picrotoxin, pentylentetrazol, strychnine) - acute or chronic seizures Topical convulsants that enhance excitation (carbachol, kainic acid) - acute seizures and chronic (kindling) models

Freeze lesion or partially isolated cortical slab (with intact vascularization) - chronic seizures Metals (Al2O3, cobalt) - chronic seizures Kindling (electrical or chemical) - chronic model Experimental febrile seizures - (acute and) chronic model

Posttraumatic epilepsy (PTE) induced by lateral fluid percussion brain injury - chronic model Hippocampal sclerosis (kainic acid, pilocarpine, poststatus epilepticus models of temporal lobe epilepsy (TLE) - chronic models Focal dysplasia (neonatal freeze, prenatal radiation, methylazoxymethanol) - neonatal, prenatal treatment models

Table 22.2 Generalized epilepsy models (Modified from Holmes 2004; Bagdy et al. 2007) Genetics

Genetically epilepsy prone rats (GEPRs)

Mongolian gerbil

DBA/2 J mouse

Chromosome 4 congenic mice

Photosensitive baboon

5-HT2C receptor knock out mice

5-HT1A receptor knock out mice

Generalized tonic-clonic seizure

Maximal electroshock (MES)

Chemoconvulsant

Glutamate agonists

• Pilocarpine GABA antagonists

• Pentylentetrazol

• Bicuculline

• Picrotoxin Other Absence

Genetic absence rats from Strasburg (GAERS) Wistar Albino Glaxo/Rijswijk (WAG/Rij) Low-dose penthylenetetrazol

Cholesterol biosynthesis inhibitor (AY-994) - atypical Mice

• Slow-wave epilepsy mice

Maximal electroshock and chemoconvulsants are useful in generating acute seizures but are not adequate models for studying epilepsy. While spontaneous recurrent seizures can occur following status epilepticus induced by chemoconvulsants, the seizures usually are partial with secondary generalization.

The basic underlying mechanism in absence seizure, characterized by the generation of intermittent synchronized bursting of neurons separated by periods of normal function, arises from thalamus-cortex interaction. During spike and wave discharges, a large number of neurons oscillate between short periods of excitation, corresponding to the spike, and longer periods of inhibition, corresponding to the slow wave component of the spike and wave complex (Gloor 1978). Both in vivo and in vitro studies have demonstrated the neuronal circuit that generates the oscillatory thalamocortical burst firing observed during absence seizures (Snead 1995). Within the thalamus, sleep spindles are generated as a recurrent interaction between thalamocortical and thalamic reticular cells (Steriade et al. 1993). It has been suggested, based on the resemblance in the EEG and the similar circadian pattern, that spike-wave discharges (SWD) are modified sleep spindles (Steriade et al. 1993; McCormick 2002). Spike-wave discharges never develop in genetic rat absence models with lesions in their thalamic reticular nucleus, which is considered the primary pacemaker of spindle rhythm. In idiopathic generalized epilepsy, spindles transform to SWD pattern; in other words, SWD represent the epileptic variant of the complex thalamocortical system function, which is the substrate of non-REM sleep EEG phenomena (Halasz et al. 2002). The circuit comprises only three neuronal populations: cortical pyramidal neurons, thalamocortical relay neurons, and neurons of nucleus reticularis thalami (NRT). The principal synaptic connections of the thalamocortical circuit include glutamatergic fibers between neocortical pyramidal cells and the NRT, y-aminobutyric acid (GABA)-ergic fibers from NRT neurons that activate GABAa and GABAb receptors on thalamic relay neurons, and recurrent collateral GABA-ergic fibers from NRT neurons that activate GABAA receptors on adjacent NRT neurons. Thalamic relay neurons and NRT neurons possess low-threshold, transient Ca2+ channels (T-type Ca2+ channels) that allow them to exhibit a burst firing mode, followed by an inactive mode. Mild depolarization of these neurons is sufficient to activate these T-type Ca2+ channels and to allow the influx of extracellular Ca2+. Further depolarization produced by Ca2+ inflow often exceeds the threshold for firing a burst of action potentials. After T-type Ca2+ channels are activated, they become inactivated quite quickly; hence the name transient. T-type Ca2+ channels require a long, intense hyperpolarization to remove their activation (deinactivation). The required hyperpolarization can be provided by GABAB receptors that are present on thalamic relay neurons. The interplay between GABAB-mediated inhibition and the low threshold T-type calcium channel therefore plays a critical role in generating the oscillating hyperpolarization/depolarization activity seen in the thalamus. In animal absence models, GABAB receptor agonists produce an increase in seizure frequency (by facilitating deinactivation of T-type Ca2+ channels), whereas GABAB receptor antagonists reduce seizure frequency.

As noted earlier, collateral GABA-ergic fibers from the NRT neurons activate GABAA receptors on adjacent NRT neurons. Activating GABAA receptors in NRT, therefore, results in reduction of GABA-ergic output to the thalamic relay neurons. a-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors appear to mediate fast transmission in the thalamus. According to data derived from the computational models that produce spike-wave oscillations, both AMPA and GABAB receptors interact during the generation and propagation of the oscillations (Destexhe et al. 1996). Thalamocortical relay cells can elicit AMPA receptor-mediated excitatory postsynaptic potentials in NRT, while the latter neurons elicit GABAA and GABAB-related inhibitory postsynaptic potentials, generating continuous oscillations. Kaminski et al. (2001) found that GABAb and AMPA receptors-mediated neurotransmission regulates the occurrence of SWD in an additive manner in WAG/Rij rats.

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