Impairment of intracortical GABAergic inhibition in a rat model of absence epilepsy

Abstract

The WAG/Rij rat strain is characterized in its EEG by the manifestation of spike-wave discharges which resemble in their spontaneous appearance and pharmacological sensitivity the absence epilepsy observed in humans. In order to test the hypothesis whether cellular intrinsic membrane and/or synaptic network properties in the neocortex are modified in this form of epilepsy, we analyzed with extra-and intracellular recording techniques the functional status of neocortical slices obtained from adult epileptic WAG/Rij rats and compared them with the data acquired from non-epileptic control Wistar rats. Intrinsic membrane properties, like resting membrane potential, neuronal input resistance and basic cellular firing characteristics, did not differ between these two strains. However, the analysis of extra-and intracellularly recorded synaptic responses revealed an intracortical hyperexcitability which was accompanied by a significant reduction in the efficiency of GABAergic inhibition. Our data indicate that the imbalance between intracortical excitatory and inhibitory mechanisms may at least contribute to the expression and augmentation of spike-wave discharges in epileptic WAG/Rij rats.

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

“…Experimental evidence obtained to date from in vitro slice studies indicates that epileptic WAG/Rij neocortical neurons present with: (i) marked reduction in I h (a cation current that is known to modulate neuron excitability and rhythmicity) (Strauss et al, 2004), (ii) decreased function of GABA A receptor-mediated post-synaptic inhibition (Luhmann et al, 1995) and (iii) increased NMDA receptor-mediated events leading to prolonged depolarizing responses and to action potential discharge (Luhmann et al, 1995;D'Arcangelo et al, 2002;D'Antuono et al, 2006). The latter mechanism has also been identified in vivo both in WAG/Rij (Peeters et al, 1989) and GAERS (Pumain et al, 1992) animals.…”

“…Indeed, recent evidence points to the perioral area of the somatosensory cortex as the site of initiation of generalized SW activity in both WAG/Rij and GAERS epileptic animals (Meeren et al, 2002;Manning et al, 2004). Several in vivo and in vitro studies have shown that neocortical hyperexcitability in these genetic models is caused by changes in intrinsic (Strauss et al, 2004;Klein et al, 2004) and synaptic mechanisms (Peeters et al, 1989;Pumain et al, 1992;Luhmann et al, 1995;D'Arcangelo et al, 2002;Pinault, 2003;D'Antuono et al, 2006).…”

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…The cortical hyperexcitability in WAG/Rij rats, measured by extra-and intracellularly recorded synaptic responses, is probably due to a decrease in GABA-mediated inhibition leading to the hypothesis that the GABA effects on SWDs may depend on regional processes and are not homogeneous within the brain (Luhmann et al, 1995). Interestingly, Merlo et al indicate that these molecular changes are not seen in young (about 60days old) WAG/Rij rats that do not yet present SWDs (Merlo et al, 2007).…”

“…Altered GABA A receptor function has been described in the cerebral cortex and thalamus of WAG/Rij rats and may contribute to abnormal brain states of absence epilepsy (D'Antuono et al, 2006;Luhmann et al, 1995). In WAG/Rij rats, GABAergic inhibition is reduced in upper-layer frontal cortical neurons (Luhmann et al, 1995), and GABA A receptor-mediated fast hyperpolarizing inhibitory postsynaptic potentials (IPSPs) show decreased peak conductances in deeper-layer neurons (D'Antuono et al, 2006). WAG/Rij rats in comparison to Wistar rats, exhibited a significant reduction in the efficiency of intracortical GABAergic inhibition concomitant with hyperexcitability (Luhmann et al, 1995) and interestingly, many cortical areas are lacking parvalbumin-containing interneurons.…”

Generalized Epileptic Disorders: An Update

“…In line with this view, recent studies in slices of the ferret lateral geniculate nucleus have shown that the frequency of the rhythmic oscillations generated by geniculate neurons is controlled by the patterns of activation of corticothalamic inputs, which in these experiments were mimicked by electrical stimulation of corticothalamic fibers (92). Accordingly, several studies in genetic rodent models of absence seizures have revealed changes in neocortical excitability, including increased non-N-methyl-Daspartate (NMDA)-and NMDA-receptor mediated excitatory synaptic transmission (74,89,90) and decreased GABA-mediated inhibition (89,93). Overall, the expression of generalized spike-and-wave discharges during absence seizures in most animal models requires the function of reciprocally connected thalamic and cortical networks.…”