Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus
Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitoto...
| Autores: | , , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2024 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositório: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/377768 |
| Acesso em linha: | http://hdl.handle.net/10261/377768 |
| Access Level: | Acceso aberto |
| Palavra-chave: | DREADDs FDG PET astrocyte excitotoxicity metabolism. |
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Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampusHernández-Martín, N.Martínez, M.G.Bascuñana, PabloFernandez de la Rosa, RubenGarcía-García, LuisGómez, FranciscaSolas, M. TeresaMartín, Eduardo D.Pozo, Miguel A.DREADDsFDG PETastrocyteexcitotoxicitymetabolism.Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity-induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild-type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2-deoxy-2-[F]-fluoro-D-glucose (F-FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca activation increased the F-FDG uptake, but this effect was not found when the study was performed in knock out mice for type-2 inositol 1,4,5-trisphosphate receptor (Ip3r2) nor in floxed mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA-induced damage. This evidence suggests a protective role of activated astrocytes against KA-induced excitotoxicity.This work was financially supported by Spanish Agencia Estatal de Investigación (AEI), Ministerio de Ciencia, Innovación y Universidades (MCIU) (AEI/10.13039/501100011033—M.A.P.: PDI2019-106968RB-100; E.D.M.: PID2020-116327GB-100; M.S.: SAF2017-87619-P).P.B. position is funded by a Miguel Servet grant (Instituto de Salud Carlos III, CP21/00020). N.H.M. position is funded by Alfonso Casanava fellowship granted by Universidad Complutense de Madrid.M.G.M. position was funded by Garantía Juvenil program granted by Comunidad de Madrid.John Wiley & SonsAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Instituto de Salud Carlos IIIUniversidad Complutense de MadridComunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2025202520242025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/377768reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106968RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116327GB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87619-Phttp://dx.doi.org/10.1002/glia.24607Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3777682026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| title |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| spellingShingle |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus Hernández-Martín, N. DREADDs FDG PET astrocyte excitotoxicity metabolism. |
| title_short |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| title_full |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| title_fullStr |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| title_full_unstemmed |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| title_sort |
Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus |
| dc.creator.none.fl_str_mv |
Hernández-Martín, N. Martínez, M.G. Bascuñana, Pablo Fernandez de la Rosa, Ruben García-García, Luis Gómez, Francisca Solas, M. Teresa Martín, Eduardo D. Pozo, Miguel A. |
| author |
Hernández-Martín, N. |
| author_facet |
Hernández-Martín, N. Martínez, M.G. Bascuñana, Pablo Fernandez de la Rosa, Ruben García-García, Luis Gómez, Francisca Solas, M. Teresa Martín, Eduardo D. Pozo, Miguel A. |
| author_role |
author |
| author2 |
Martínez, M.G. Bascuñana, Pablo Fernandez de la Rosa, Ruben García-García, Luis Gómez, Francisca Solas, M. Teresa Martín, Eduardo D. Pozo, Miguel A. |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Agencia Estatal de Investigación (España) Ministerio de Ciencia, Innovación y Universidades (España) Instituto de Salud Carlos III Universidad Complutense de Madrid Comunidad de Madrid Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
DREADDs FDG PET astrocyte excitotoxicity metabolism. |
| topic |
DREADDs FDG PET astrocyte excitotoxicity metabolism. |
| description |
Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity-induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild-type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2-deoxy-2-[F]-fluoro-D-glucose (F-FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca activation increased the F-FDG uptake, but this effect was not found when the study was performed in knock out mice for type-2 inositol 1,4,5-trisphosphate receptor (Ip3r2) nor in floxed mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA-induced damage. This evidence suggests a protective role of activated astrocytes against KA-induced excitotoxicity. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2025 2025 2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10261/377768 |
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http://hdl.handle.net/10261/377768 |
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Inglés |
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Inglés |
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#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106968RB-I00 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116327GB-I00 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-87619-P http://dx.doi.org/10.1002/glia.24607 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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John Wiley & Sons |
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John Wiley & Sons |
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