High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy

Objective: Pharmacoresistance and the lack of disease-modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs,...

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Autores: Conte, Giorgia, Parras, Alberto, Alves, Mariana, Ollá, Ivanna, Diego-García, Laura de, Beamer, Edward, Alalqam, Razi, Ocampo, Alejandro, Méndez, Raúl, Henshall, David C., Lucas, José Javier, Engel, Tobías
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/241725
Acceso en línea:http://hdl.handle.net/10261/241725
Access Level:acceso abierto
Palabra clave:Calcium signaling
CREB
Epilepsy
Mouse model
Status epilepticus
Transcriptomes
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spelling High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsyConte, GiorgiaParras, AlbertoAlves, MarianaOllá, IvannaDiego-García, Laura deBeamer, EdwardAlalqam, RaziOcampo, AlejandroMéndez, RaúlHenshall, David C.Lucas, José JavierEngel, TobíasCalcium signalingCREBEpilepsyMouse modelStatus epilepticusTranscriptomesObjective: Pharmacoresistance and the lack of disease-modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra-amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). Methods: Status epilepticus was induced via intra-amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. Results: Intra-amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element-binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra-amygdala kainic acid model. Significance: Our findings suggest the intra-amygdala kainic acid model faithfully replicates key molecular features of human drug-resistant TLE and provides potential rational target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.Number: HRA-POR-2015-1243; Science Foundation Ireland, Grant/Award Number: 16/RC/3948 and 17/CDA/4708; H2020 Environment, Grant/Award Number: 753527, 766124 and 796600; Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, Grant/Award Number: PI2015-2/06-3 and PI2018/06-1; Ministerio de Economia y Competitividad, Grant/Award Number: SAF2015-65371-R; Ministerio de Ciencia, Innovacion y Universidades, Grant/Award Number: RTI2018-096322-B-I00Blackwell PublishingScience Foundation IrelandCentro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Ministerio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120202021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/241725reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1111/epi.16714Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2417252026-05-22T06:33:51Z
dc.title.none.fl_str_mv High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
title High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
spellingShingle High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
Conte, Giorgia
Calcium signaling
CREB
Epilepsy
Mouse model
Status epilepticus
Transcriptomes
title_short High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
title_full High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
title_fullStr High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
title_full_unstemmed High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
title_sort High concordance between hippocampal transcriptome of the mouse intra-amygdala kainic acid model and human temporal lobe epilepsy
dc.creator.none.fl_str_mv Conte, Giorgia
Parras, Alberto
Alves, Mariana
Ollá, Ivanna
Diego-García, Laura de
Beamer, Edward
Alalqam, Razi
Ocampo, Alejandro
Méndez, Raúl
Henshall, David C.
Lucas, José Javier
Engel, Tobías
author Conte, Giorgia
author_facet Conte, Giorgia
Parras, Alberto
Alves, Mariana
Ollá, Ivanna
Diego-García, Laura de
Beamer, Edward
Alalqam, Razi
Ocampo, Alejandro
Méndez, Raúl
Henshall, David C.
Lucas, José Javier
Engel, Tobías
author_role author
author2 Parras, Alberto
Alves, Mariana
Ollá, Ivanna
Diego-García, Laura de
Beamer, Edward
Alalqam, Razi
Ocampo, Alejandro
Méndez, Raúl
Henshall, David C.
Lucas, José Javier
Engel, Tobías
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Science Foundation Ireland
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)
Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Calcium signaling
CREB
Epilepsy
Mouse model
Status epilepticus
Transcriptomes
topic Calcium signaling
CREB
Epilepsy
Mouse model
Status epilepticus
Transcriptomes
description Objective: Pharmacoresistance and the lack of disease-modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra-amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). Methods: Status epilepticus was induced via intra-amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. Results: Intra-amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element-binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra-amygdala kainic acid model. Significance: Our findings suggest the intra-amygdala kainic acid model faithfully replicates key molecular features of human drug-resistant TLE and provides potential rational target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
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
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/241725
url http://hdl.handle.net/10261/241725
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1111/epi.16714
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Blackwell Publishing
publisher.none.fl_str_mv Blackwell Publishing
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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