Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis
Accumulating evidence indicate that astrocytes are essential players of the excitatory and inhibitory signaling during normal and epileptiform activity via uptake and release of gliotransmitters, ions, and other substances. Polyamines can be regarded as gliotransmitters since they are almost exclusi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2021.787319/full |
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| author | Zsolt Kovács Serguei N. Skatchkov Serguei N. Skatchkov Rüdiger W. Veh Zsolt Szabó Krisztina Németh Pál T. Szabó Julianna Kardos László Héja |
| author_facet | Zsolt Kovács Serguei N. Skatchkov Serguei N. Skatchkov Rüdiger W. Veh Zsolt Szabó Krisztina Németh Pál T. Szabó Julianna Kardos László Héja |
| author_sort | Zsolt Kovács |
| collection | DOAJ |
| description | Accumulating evidence indicate that astrocytes are essential players of the excitatory and inhibitory signaling during normal and epileptiform activity via uptake and release of gliotransmitters, ions, and other substances. Polyamines can be regarded as gliotransmitters since they are almost exclusively stored in astrocytes and can be released by various mechanisms. The polyamine putrescine (PUT) is utilized to synthesize GABA, which can also be released from astrocytes and provide tonic inhibition on neurons. The polyamine spermine (SPM), synthesized form PUT through spermidine (SPD), is known to unblock astrocytic Cx43 gap junction channels and therefore facilitate astrocytic synchronization. In addition, SPM released from astrocytes may also modulate neuronal NMDA, AMPA, and kainate receptors. As a consequence, astrocytic polyamines possess the capability to significantly modulate epileptiform activity. In this study, we investigated different steps in polyamine metabolism and coupled GABA release to assess their potential to control seizure generation and maintenance in two different epilepsy models: the low-[Mg2+] model of temporal lobe epilepsy in vitro and in the WAG/Rij rat model of absence epilepsy in vivo. We show that SPM is a gliotransmitter that is released from astrocytes and significantly contributes to network excitation. Importantly, we found that inhibition of SPD synthesis completely prevented seizure generation in WAG/Rij rats. We hypothesize that this antiepileptic effect is attributed to the subsequent enhancement of PUT to GABA conversion in astrocytes, leading to GABA release through GAT-2/3 transporters. This interpretation is supported by the observation that antiepileptic potential of the Food and Drug Administration (FDA)-approved drug levetiracetam can be diminished by specifically blocking astrocytic GAT-2/3 with SNAP-5114, suggesting that levetiracetam exerts its effect by increasing surface expression of GAT-2/3. Our findings conclusively suggest that the major pathway through which astrocytic polyamines contribute to epileptiform activity is the production of GABA. Modulation of astrocytic polyamine levels, therefore, may serve for a more effective antiepileptic drug development in the future. |
| first_indexed | 2024-04-11T20:56:03Z |
| format | Article |
| id | doaj.art-f14038e633db47939b9cde41b3db79e6 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-11T20:56:03Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-f14038e633db47939b9cde41b3db79e62022-12-22T04:03:42ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-01-011510.3389/fncel.2021.787319787319Critical Role of Astrocytic Polyamine and GABA Metabolism in EpileptogenesisZsolt Kovács0Serguei N. Skatchkov1Serguei N. Skatchkov2Rüdiger W. Veh3Zsolt Szabó4Krisztina Németh5Pál T. Szabó6Julianna Kardos7László Héja8Department of Biology, ELTE Eötvös Loránd University, Savaria University Centre, Szombathely, HungaryDepartment of Physiology, Universidad Central Del Caribe, Bayamon, PR, United StatesDepartment of Biochemistry, Universidad Central Del Caribe, Bayamon, PR, United StatesInstitut für Zell- und Neurobiologie, Centrum 2, Charité - Universitätsmedizin Berlin, Berlin, GermanyFunctional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, HungaryMS Metabolomics Research Group, Centre for Structural Study, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, HungaryMS Metabolomics Research Group, Centre for Structural Study, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, HungaryFunctional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, HungaryFunctional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, HungaryAccumulating evidence indicate that astrocytes are essential players of the excitatory and inhibitory signaling during normal and epileptiform activity via uptake and release of gliotransmitters, ions, and other substances. Polyamines can be regarded as gliotransmitters since they are almost exclusively stored in astrocytes and can be released by various mechanisms. The polyamine putrescine (PUT) is utilized to synthesize GABA, which can also be released from astrocytes and provide tonic inhibition on neurons. The polyamine spermine (SPM), synthesized form PUT through spermidine (SPD), is known to unblock astrocytic Cx43 gap junction channels and therefore facilitate astrocytic synchronization. In addition, SPM released from astrocytes may also modulate neuronal NMDA, AMPA, and kainate receptors. As a consequence, astrocytic polyamines possess the capability to significantly modulate epileptiform activity. In this study, we investigated different steps in polyamine metabolism and coupled GABA release to assess their potential to control seizure generation and maintenance in two different epilepsy models: the low-[Mg2+] model of temporal lobe epilepsy in vitro and in the WAG/Rij rat model of absence epilepsy in vivo. We show that SPM is a gliotransmitter that is released from astrocytes and significantly contributes to network excitation. Importantly, we found that inhibition of SPD synthesis completely prevented seizure generation in WAG/Rij rats. We hypothesize that this antiepileptic effect is attributed to the subsequent enhancement of PUT to GABA conversion in astrocytes, leading to GABA release through GAT-2/3 transporters. This interpretation is supported by the observation that antiepileptic potential of the Food and Drug Administration (FDA)-approved drug levetiracetam can be diminished by specifically blocking astrocytic GAT-2/3 with SNAP-5114, suggesting that levetiracetam exerts its effect by increasing surface expression of GAT-2/3. Our findings conclusively suggest that the major pathway through which astrocytic polyamines contribute to epileptiform activity is the production of GABA. Modulation of astrocytic polyamine levels, therefore, may serve for a more effective antiepileptic drug development in the future.https://www.frontiersin.org/articles/10.3389/fncel.2021.787319/fullabsence epilepsyWAG/Rij rat modelAPCHA/spermine synthase inhibitor4-MCHA/spermidine synthase inhibitorpolyamines in the central nervous systemneurons |
| spellingShingle | Zsolt Kovács Serguei N. Skatchkov Serguei N. Skatchkov Rüdiger W. Veh Zsolt Szabó Krisztina Németh Pál T. Szabó Julianna Kardos László Héja Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis Frontiers in Cellular Neuroscience absence epilepsy WAG/Rij rat model APCHA/spermine synthase inhibitor 4-MCHA/spermidine synthase inhibitor polyamines in the central nervous system neurons |
| title | Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis |
| title_full | Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis |
| title_fullStr | Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis |
| title_full_unstemmed | Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis |
| title_short | Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis |
| title_sort | critical role of astrocytic polyamine and gaba metabolism in epileptogenesis |
| topic | absence epilepsy WAG/Rij rat model APCHA/spermine synthase inhibitor 4-MCHA/spermidine synthase inhibitor polyamines in the central nervous system neurons |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2021.787319/full |
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