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
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 model...
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Elsevier
2020-09-01
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| Series: | Brain Stimulation |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1935861X20302114 |
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| author | Elena Y. Smirnova Anton V. Chizhov Aleksey V. Zaitsev |
| author_facet | Elena Y. Smirnova Anton V. Chizhov Aleksey V. Zaitsev |
| author_sort | Elena Y. Smirnova |
| collection | DOAJ |
| description | 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 GABAA, GABAB, AMPA, or NMDA synaptic receptors strongly affected the characteristics of epileptiform discharges in slices. However, only under the blockade of GABAB receptors, LFES becomes entirely ineffective, indicating that the activation of GABAB receptors underlies the main LFES antiepileptic effect. Further experiments allowed us to suggest that LFES activates mostly presynaptic GABAB 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 GABAB 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 GABAB receptors in the antiepileptic effect of LFES in the 4-AP model in juvenile rat brain slices. |
| first_indexed | 2024-12-14T01:18:45Z |
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| id | doaj.art-75f2b5f8d98d47fd8151fa3b036cf332 |
| institution | Directory Open Access Journal |
| issn | 1935-861X |
| language | English |
| last_indexed | 2024-12-14T01:18:45Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
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| series | Brain Stimulation |
| spelling | doaj.art-75f2b5f8d98d47fd8151fa3b036cf3322022-12-21T23:22:30ZengElsevierBrain Stimulation1935-861X2020-09-0113513871395Presynaptic GABAB receptors underlie the antiepileptic effect of low-frequency electrical stimulation in the 4-aminopyridine model of epilepsy in brain slices of young ratsElena Y. Smirnova0Anton V. Chizhov1Aleksey V. Zaitsev2Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS (IEPhB), 44, Toreza Prospekt, St. Petersburg, 194223, Russia; Almazov National Medical Research Centre, Institute of Experimental Medicine, 2 Akkuratova Street, St. Petersburg, 197341, Russia; Corresponding author. Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS (IEPhB), 44, Toreza Prospekt, St. Petersburg, 194223, Russia.Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS (IEPhB), 44, Toreza Prospekt, St. Petersburg, 194223, Russia; Ioffe Institute, 26, Politekhnicheskaya, St Petersburg, 194021, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry of RAS (IEPhB), 44, Toreza Prospekt, St. Petersburg, 194223, Russia; Almazov National Medical Research Centre, Institute of Experimental Medicine, 2 Akkuratova Street, St. Petersburg, 197341, RussiaLow-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 GABAA, GABAB, AMPA, or NMDA synaptic receptors strongly affected the characteristics of epileptiform discharges in slices. However, only under the blockade of GABAB receptors, LFES becomes entirely ineffective, indicating that the activation of GABAB receptors underlies the main LFES antiepileptic effect. Further experiments allowed us to suggest that LFES activates mostly presynaptic GABAB 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 GABAB 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 GABAB receptors in the antiepileptic effect of LFES in the 4-AP model in juvenile rat brain slices.http://www.sciencedirect.com/science/article/pii/S1935861X20302114EpilepsyLow-frequency electrical stimulation4-Aminopyridine modelEntorhinal cortexIctal dischargePresynaptic GABAB receptor |
| spellingShingle | Elena Y. Smirnova Anton V. Chizhov Aleksey V. Zaitsev 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 Brain Stimulation Epilepsy Low-frequency electrical stimulation 4-Aminopyridine model Entorhinal cortex Ictal discharge Presynaptic GABAB receptor |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Epilepsy Low-frequency electrical stimulation 4-Aminopyridine model Entorhinal cortex Ictal discharge Presynaptic GABAB receptor |
| url | http://www.sciencedirect.com/science/article/pii/S1935861X20302114 |
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