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Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus

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dc.contributor.authorGonzalez-Ramos, Ana
dc.contributor.authorBerglind, Fredrik
dc.contributor.authorKudláček, Jan
dc.contributor.authorRibeiro Rocha, Elza
dc.contributor.authorMelin, Esbjörn
dc.contributor.authorSebastião, Ana M
dc.contributor.authorValente, Cláudia A.
dc.contributor.authorLedri, Marco
dc.contributor.authorAndersson, My
dc.contributor.authorKokaia, Merab
dc.date.accessioned2025-06-11T14:50:18Z
dc.date.available2025-06-11T14:50:18Z
dc.date.issued2024
dc.description© The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/.pt_PT
dc.description.abstractDespite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.pt_PT
dc.description.sponsorshipThis project was funded by the European Union Horizon 2020 Program (H2020-MSCA-ITN-2016) under the Marie Skłodowska-Curie Innovative Training Network, project Training4CRM Grant Agreement No. 722779. This project was also funded by the Swedish Research Council (Grant Number: 2017-00921, MK; and 2016-02605, MA), the Swedish Brain Foundation F02021-0369 (MA), and Crafoord Foundation (MA). In addition, the collaborative effort reflected in this study was funded by the European Union Horizon 2020 Program (H2020-WIDESPREAD-2020-5), EpiEpiNet project Grant agreement ID: 952455, grant from the Ministry of Health of the Czech Republic (NU21-08-00533) and grant from the Charles University Primus/26/MED/011. Open access funding provided by Lund University.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGene Ther. 2025 Mar;32(2):106-120pt_PT
dc.identifier.doi10.1038/s41434-024-00493-7pt_PT
dc.identifier.eissn1476-5462
dc.identifier.issn0969-7128
dc.identifier.urihttp://hdl.handle.net/10400.5/101499
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationEuropean Training Network for Cell-based Regenerative Medicine
dc.relationEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
dc.relation.publisherversionhttps://www.nature.com/gt/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleChemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampuspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumber722779
oaire.awardNumber952455
oaire.awardTitleEuropean Training Network for Cell-based Regenerative Medicine
oaire.awardTitleEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/722779/EU
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/952455/EU
oaire.citation.endPage120pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage106pt_PT
oaire.citation.titleGene Therapypt_PT
oaire.citation.volume32pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamH2020
person.familyNameRibeiro Rocha
person.familyNameSebastião
person.familyNameValente
person.givenNameElza
person.givenNameAna M
person.givenNameCláudia
person.identifier.ciencia-id9B1C-71C2-C181
person.identifier.ciencia-idF112-55E8-E37E
person.identifier.ciencia-idBD1B-6720-D51D
person.identifier.orcid0000-0001-7155-6151
person.identifier.orcid0000-0001-9030-6115
person.identifier.orcid0000-0001-5405-3130
person.identifier.ridA-3868-2013
person.identifier.scopus-author-id7004409879
person.identifier.scopus-author-id9842734300
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication50d3306b-dfc3-4ac6-acb2-2c226bcc60a2
relation.isAuthorOfPublication304abd7f-071b-4447-a8a3-4aa5f0547141
relation.isAuthorOfPublicationf8ed7487-bd16-460b-9e4f-ef0ca623b5ba
relation.isAuthorOfPublication.latestForDiscovery304abd7f-071b-4447-a8a3-4aa5f0547141
relation.isProjectOfPublication28873234-b34c-4d2e-9496-e2aae56ef959
relation.isProjectOfPublication71376ce5-3732-4d41-b053-3dad707d6191
relation.isProjectOfPublication.latestForDiscovery28873234-b34c-4d2e-9496-e2aae56ef959

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