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

Abstract

GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

KCC2 function modulates in vitro ictogenesis

“…Indeed, early work in the in vitro hippocampal slice preparation demonstrated that interictal-like (hereafter referred to as interictal) epileptiform activity results from weakened inhibition (Johnston and Brown, 1981;Prince, 1978, 1980) but later, by employing experimental procedures that enhance GABAergic signaling such as the K + channel blocker 4-aminopyridine (4AP) or Mg 2+ free medium, we and other investigators have reported that ictal-like (hereafter referred to as ictal) discharges in adult rodents are paradoxically contributed by GABA A receptor-mediated signaling (see for review Avoli and de Curtis, 2011). In addition, under specific pharmacological manipulations, GABA A receptor-mediated currents are the sole synaptic mechanism contributing to ictogenesis in the hippocampus (Uusisaari et al, 2002).…”

Models of drug-induced epileptiform synchronization in vitro

“…In line with this view, measurements of the extracellular [K + ] elevations associated with the "slow" 4AP-induced interictal events occurring during blockade of glutamatergic transmission have shown larger values in juvenile than in adult hippocampal slices (Avoli et al, 1996b). However, in line with what originally reported by Galvan et al (1982), ictal-like activity is readily generated in response to 4AP application by neuronal networks in several limbic and extralimbic structures such as the rhinal cortices, the amygdala, and the insular or cingular cortices (Avoli et al, 1996a;Brückner and Heinemann, 2000;Klueva et al, 2003; see for review Avoli and de Curtis, 2011). By employing the in vitro isolated hippocampus from new-born rats Luhmann et al (2000) have shown that 4AP can induce interictal and ictal discharges in the CA3 area as well as that these events can propagate to the entorhinal cortex when animals older than 3 days are used.…”

“…As discussed above, slow interictal discharges induced by 4AP are associated with transient increases in extracellular [K + ] due to the activation of GABA A receptors (Morris et al, 1996) and more specifically to the activation of the KCC2 co-transporter, which causes the extracellular efflux of both K + and Cl − (Viitanen et al, 2010). As reviewed by Avoli and de Curtis (2011), such increases in extracellular K + are expected to depolarize neighbouring neurons, to promote ectopic spike generation, and to shift the reversal potential of GABA A receptor-mediated IPSPs in a positive direction, thus weakening inhibition. All these mechanisms, which are paradoxically initiated by the activation of GABA A receptor signalling, are known to increase neuronal excitability and are thus likely to promote ictogenesis in the 4AP in vitro brain slice model.…”

“…Remarkably, the pharmacological characteristics of the 4AP-induced epileptiform discharges recorded from the isolated hippocampus were very similar to those identified in the young rat hippocampal slice preparation (Avoli et al, 1996b) since they were abolished by non-NMDA receptor antagonists while they were not significantly influenced by drugs that blocked the NMDA receptor. In contrast, ictal discharges generated by adult limbic areas in brain slices bathed in 4AP containing medium are highly sensitive to both NMDA and non-NMDA glutamatergic receptor antagonists (see for review Avoli and de Curtis, 2011).…”

“…Slices of the in young hippocampus as well as those obtained from several adult limbic structures generate, during 4AP application, ictal discharges that are initiated by synchronous events that reflect the firing of GABA releasing cells thus suggesting the involvement of GABA in ictogenesis (Avoli and de Curtis, 2011). This hypothesis has recently been tested with optogenetic techniques in the entorhinal cortex during 4AP treatment (Shiri et al, 2015;Yekhlef et al, 2015); these experiments have shown that optogenetic activation of parvalbumin-or somatostatin-positive interneurons can elicit ictal discharges that are similar to those occurring spontaneously, including their association with initial isolated spikes that are caused by the optogenetic stimulation of interneurons.…”