Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

Abstract

Mechanisms involved in the transition to an epileptic seizure remain unclear. We studied this question in tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability together with an alkalinization or low Mg 2+ . During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of epileptic subjects revealed similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster, have a larger amplitude and a distinct initiation site than interictal discharges. They depend on glutamatergic mechanisms and are preceded by pyramidal cell firing, while interneuron firing precedes interictal events which depend on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggers seizures. Thus the subiculum supports seizure generation and the transition to seizure involves a novel, emergent glutamatergic population activity.3

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Similar results have recently been published by Huberfeld et al (2011) who studied the transition from interictal-to ictal-like epileptiform discharges in the subiculum of brain slices that were obtained from TLE patients undergoing surgery. It should be noted that in order to obtain a pattern of ictal-like activity these authors had to employ multiple pharmacological manipulations of the superfusing medium including high K + , low Mg 2+ and Ca 2+ , or external alkalinization, since a "single" manipulation consisiting of bath application of 4AP, high K + , low Mg 2+ or bicuculline failed in inducing ictal-like events.…”

“…It should be noted that in order to obtain a pattern of ictal-like activity these authors had to employ multiple pharmacological manipulations of the superfusing medium including high K + , low Mg 2+ and Ca 2+ , or external alkalinization, since a "single" manipulation consisiting of bath application of 4AP, high K + , low Mg 2+ or bicuculline failed in inducing ictal-like events. In these experiments, Huberfeld et al (2011) found that distinct pre-ictal discharges, which emerged concurrently with interictal events, depend on glutamatergic mechanisms and are preceded by pyramidal cell firing, whereas interneuron firing precedes interictal events that depend on both glutamatergic and depolarizing GABAergic signaling; moreover, preictal spikes spread faster that interictal-like discharges suggesting a reduced inhibitory restraint.…”

“…However, synchronous interneuronal firing leads to GABA release thus promoting a large increase in [K + ] o ; this in turn restores neuronal firing in all cells and promotes the transition into the massive, synchronous activity typically observed during the full-blown phase of a seizure (Trombin et al, 2011). An alternative hypothesis (blue dotted line) is based on data obtained in the CA1/subiculum area by Derchansky et al (2008), Ziburkus et al (2006) and Huberfeld et al (2011). According to these findings principal glutamatergic cells are massively recruited in the pre-ictal phase and the consequent synaptic release of glutamate along with the [K + ] o increase promote the transition into seizure; hence, in this type of preictal stage interneurons are secondarily activated by principal glutamatergic cells.…”

“…Therefore, in the experiments performed by Ziburkus et al (2006) and by Derchansky et al (2008) in rodent slices as well as in human recordings of Huberfeld et al (2011), GABA A receptor-mediated mechanisms -which are operative and enhanced during the interictal period -appear to fade away in the preictal phase and even more once the ictal activity occurs. Whether the different results obtained in the 4AP model (in which mostly GABAergic spikes appear to initiate ictal-like activity) are due to differences in drug treatment, brain structure analyzed or maturity of the tissue remains a matter of discussion.…”

Mechanisms of physiological and epileptic HFO generation

“…During the progressive recruitment to a seizure, before GABAergic inhibition weakens and an ever growing excitatory drive starts to dominate the firing dynamics (Dzhala and Staley, 2003;Huberfeld et al, 2011;Jiruska et al, 2010a;Timofeev and Steriade, 2004;Trevelyan et al, 2006), there is a major contribution of synchronous GABAergic potentials to HFO in the beta (20-30 Hz) and the gamma range (40-120 Hz) (Gnatkovsky et al, 2008;Köhling et al, 2000;Trevelyan et al, 2006;Trevelyan, 2009). Later on, this rhythmic GABAergic inhibition progressively decreases driven by the collapse of chloride gradients together with a desychronization of interneuronal firing (Derchansky et al, 2008;Dzhala et al, 2010;Gnatkovsky et al, 2008;Lasztoczi et al, 2009;Timofeev et al, 2002b;Viitanen et al, 2010).…”