Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy

Astrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communic...

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Autores: Fernández, Sara (Fernández García), Sancho Balsells, Anna, Longueville, Sophie, Hervé, Denis, Gruart i Massó, Agnès, Delgado García, José M., Alberch i Vié, Jordi, 1959-, Giralt Torroella, Albert
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/183399
Acceso en línea:https://hdl.handle.net/2445/183399
Access Level:acceso abierto
Palabra clave:Models animals en la investigació
Astròcits
Epilèpsia
Animal models in research
Astrocytes
Epilepsy
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spelling Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsyFernández, Sara (Fernández García)Sancho Balsells, AnnaLongueville, SophieHervé, DenisGruart i Massó, AgnèsDelgado García, José M.Alberch i Vié, Jordi, 1959-Giralt Torroella, AlbertModels animals en la investigacióAstròcitsEpilèpsiaAnimal models in researchAstrocytesEpilepsyAstrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.Nature Publishing Group2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/183399Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41419-020-2615-9Cell Death and Disease, 2020, vol. 11, num. 6, p. 411https://doi.org/10.1038/s41419-020-2615-9cc-by-nc-sa (c) Fernández, Sara (Fernández García) et al., 2020https://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1833992026-05-27T06:46:51Z
dc.title.none.fl_str_mv Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
title Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
spellingShingle Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
Fernández, Sara (Fernández García)
Models animals en la investigació
Astròcits
Epilèpsia
Animal models in research
Astrocytes
Epilepsy
title_short Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
title_full Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
title_fullStr Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
title_full_unstemmed Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
title_sort Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
dc.creator.none.fl_str_mv Fernández, Sara (Fernández García)
Sancho Balsells, Anna
Longueville, Sophie
Hervé, Denis
Gruart i Massó, Agnès
Delgado García, José M.
Alberch i Vié, Jordi, 1959-
Giralt Torroella, Albert
author Fernández, Sara (Fernández García)
author_facet Fernández, Sara (Fernández García)
Sancho Balsells, Anna
Longueville, Sophie
Hervé, Denis
Gruart i Massó, Agnès
Delgado García, José M.
Alberch i Vié, Jordi, 1959-
Giralt Torroella, Albert
author_role author
author2 Sancho Balsells, Anna
Longueville, Sophie
Hervé, Denis
Gruart i Massó, Agnès
Delgado García, José M.
Alberch i Vié, Jordi, 1959-
Giralt Torroella, Albert
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Models animals en la investigació
Astròcits
Epilèpsia
Animal models in research
Astrocytes
Epilepsy
topic Models animals en la investigació
Astròcits
Epilèpsia
Animal models in research
Astrocytes
Epilepsy
description Astrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/183399
url https://hdl.handle.net/2445/183399
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41419-020-2615-9
Cell Death and Disease, 2020, vol. 11, num. 6, p. 411
https://doi.org/10.1038/s41419-020-2615-9
dc.rights.none.fl_str_mv cc-by-nc-sa (c) Fernández, Sara (Fernández García) et al., 2020
https://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-sa (c) Fernández, Sara (Fernández García) et al., 2020
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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