Presynaptic GABAB receptors underlie the antiepileptic effect of low-frequency electrical stimulation in the 4-aminopyridine model of epilepsy in brain slices of young rats

Abstract

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.

Short-Term Epileptiform Activity Potentiates Excitatory Synapses but Does Not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus In Vitro

“…In the presented work, we did not reveal presynaptic changes after epileptiform activity. The application of 4-AP affects the paired-pulse ratio, and during continuous perfusion of brain slices with 4-AP paired-pulse facilitation, turns into paired-pulse depression [9,54,55], suggesting an increase in neurotransmitter release probability. The frequency of mEPSCs was also significantly elevated during 4-AP-induced epileptiform activity, supporting that idea [9].…”

Short-term Epileptiform Activity Potentiates Excitatory Synapses but does not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus <em>in Vitro</em>

“…In the presented work, we did not reveal presynaptic changes after epileptiform activity. The application of 4-AP affects the paired-pulse ratio, and during continuous perfusion of brain slices with 4-AP paired-pulse facilitation turns into paired-pulse depression [9,52,53], suggesting an increase in neurotransmitter release probability. The frequency of mEPSCs was also significantly elevated during 4-AP-induced epileptiform activity, supporting that idea [9].…”

Ictal wavefront propagation in slices and simulations with conductance-based refractory density model

“…We induced the epileptiform activity in rat brain slices and performed the simultaneous recordings of the synaptic currents and the [K + ] o fluctuations (Fig 1A). The epileptiform activity in the implemented in vitro model was described in detail in our previous works [21,29,30]. Briefly, two main types of epileptiform discharges were observed: GABA-mediated IIDs (marked with blue arrows in Fig 1A ) and subsequent IDs (marked with brown arrows in Fig 1A ), which are mediated by both GABA and glutamate.…”