Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype

LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predispositio...

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Authors: García López, Raquel, Pombero, Ana, Estirado, Alicia, Geijo-Barrientos, Emilio, Martínez, Salvador
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/267606
Online Access:http://hdl.handle.net/10261/267606
Access Level:Open access
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spelling Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotypeGarcía López, RaquelPombero, AnaEstirado, AliciaGeijo-Barrientos, EmilioMartínez, SalvadorLIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.This work was supported by the Generalitat Valenciana (Prometeo/2018/041); MINECO/AEI/ERDF, EU, Spanish Ministry of Economy, Industry and Competitiveness, the Spanish State Research Agency and the European Union through the European Regional Development Fund (ERDF) – “Una manera de hacer Europa” (SAF2017-83702-R); and Instituto de Salud Carlos III (“RD16/001/0010”, co-funded by European Regional Development Fund/European Social Fund).Peer reviewedFrontiers MediaGeneralitat ValencianaMinisterio de Economía, Industria y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/267606reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83702-Rhttps://doi.org/10.3389/fcell.2021.693919Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2676062026-05-22T06:33:51Z
dc.title.none.fl_str_mv Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
title Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
spellingShingle Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
García López, Raquel
title_short Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
title_full Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
title_fullStr Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
title_full_unstemmed Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
title_sort Interneuron heterotopia in the Lis1 mutant mouse cortex underlies a structural and functional schizophrenia-like phenotype
dc.creator.none.fl_str_mv García López, Raquel
Pombero, Ana
Estirado, Alicia
Geijo-Barrientos, Emilio
Martínez, Salvador
author García López, Raquel
author_facet García López, Raquel
Pombero, Ana
Estirado, Alicia
Geijo-Barrientos, Emilio
Martínez, Salvador
author_role author
author2 Pombero, Ana
Estirado, Alicia
Geijo-Barrientos, Emilio
Martínez, Salvador
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Generalitat Valenciana
Ministerio de Economía, Industria y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
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/10261/267606
url http://hdl.handle.net/10261/267606
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83702-R
https://doi.org/10.3389/fcell.2021.693919
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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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