Low-frequency electrical stimulation (LFES) of the brain is one of the promising methods for helping patients with pharmacoresistant epilepsy. However, the mechanism of the antiepileptic effect of LFES is still unclear. We applied electrophysiological and pharmacological tools and mathematical modeling to investigate it. Using the 4-aminopyridine (4-AP) model of epileptiform activity in juvenile rat brain slices, we found that LFES increased the interval between ictal discharges (IDs) in the entorhinal cortex. The blockade of GABA_A, GABA_B, AMPA, or NMDA synaptic receptors strongly affected the characteristics of epileptiform discharges in slices. However, only under the blockade of GABA_B receptors, LFES becomes entirely ineffective, indicating that the activation of GABA_B receptors underlies the main LFES antiepileptic effect. Further experiments allowed us to suggest that LFES activates mostly presynaptic GABA_B receptors, which decrease the probability of glutamate release. In line with this hypothesis is the following data: 1) LFES reduces the short-term synaptic depression of excitatory postsynaptic currents similar to the agonist of GABA_B receptors SKF-97541; 2) the blockade of excitatory amino acid transporters diminishes the antiepileptic effect of LFES; 3) modeling of the effects of LFES on the probability of glutamate release with a previously proposed mathematical model of epileptiform activity Epileptor-2 also shows the increase of the interval between IDs. Our findings point out a crucial role of presynaptic GABA_B receptors in the antiepileptic effect of LFES in the 4-AP model in juvenile rat brain slices.

The mechanisms determining ictal discharge (ID) propagation are still not clear. In the present study, we aimed to examine these mechanisms in animal and mathematical models of epileptiform activity. Using double-patch and extracellular potassium ion concentration recordings in rat hippocampal-cortical slices, we observed that IDs moved at a speed of about 1 mm/s or less. The mechanisms of such slow propagation have been studied with a mathematical, conductance-based refractory density (CBRD) model that describes the GABA- and glutamatergic neuronal populations’ interactions and ion dynamics in brain tissue. The modeling study reveals two main factors triggerring IDs: (i) increased interneuronal activity leading to chloride ion accumulation and a consequent depolarizing GABAergic effect and (ii) the elevation of extracellular potassium ion concentration. The local synaptic transmission followed by local potassium ion extrusion and GABA receptor-mediated chloride ion accumulation underlies the ID wavefront’s propagation. In contrast, potassium ion diffusion in the extracellular space is slower and does not affect ID’s speed. The short discharges, constituting the ID, propagate much faster than the ID front. The accumulation of sodium ions inside neurons due to their hyperactivity and glutamatergic currents boosts the Na⁺/K⁺pump, which terminates the ID. Knowledge of the mechanism of ID generation and propagation contributes to the development of new treatments against epilepsy.