Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype

LIS1 (PAFAH1B1) plays a major role in the developing cerebral cortex, and haploinsufficient mutations cause human lissencephaly type 1. We have studied morphological and functional properties of the cerebral cortex of mutant mice harboring a deletion in the first exon of the mouse Lis1 (Pafah1b1) ge...

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Autores: Domínguez-Sala, Eduardo, Valdés-Sánchez, María Lourdes, Canals, Santiago, Reiner, Orly, Pombero, Ana, García López, Raquel, Estirado, Alicia, Pastor, Diego, Geijo-Barrientos, Emilio, Martínez, Salvador
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/286082
Acceso en línea:http://hdl.handle.net/10261/286082
Access Level:acceso abierto
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spelling Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotypeDomínguez-Sala, EduardoValdés-Sánchez, María LourdesCanals, SantiagoReiner, OrlyPombero, AnaGarcía López, RaquelEstirado, AliciaPastor, DiegoGeijo-Barrientos, EmilioMartínez, SalvadorLIS1 (PAFAH1B1) plays a major role in the developing cerebral cortex, and haploinsufficient mutations cause human lissencephaly type 1. We have studied morphological and functional properties of the cerebral cortex of mutant mice harboring a deletion in the first exon of the mouse Lis1 (Pafah1b1) gene, which encodes for the LisH domain. The Lis1/sLis1 animals had an overall unaltered cortical structure but showed an abnormal distribution of cortical GABAergic interneurons (those expressing calbindin, calretinin, or parvalbumin), which mainly accumulated in the deep neocortical layers. Interestingly, the study of the oscillatory activity revealed an apparent inability of the cortical circuits to produce correct activity patterns. Moreover, the fast spiking (FS) inhibitory GABAergic interneurons exhibited several abnormalities regarding the size of the action potentials, the threshold for spike firing, the time course of the action potential after-hyperpolarization (AHP), the firing frequency, and the frequency and peak amplitude of spontaneous excitatory postsynaptic currents (sEPSC’s). These morphological and functional alterations in the cortical inhibitory system characterize the Lis1/sLis1 mouse as a model of mild lissencephaly, showing a phenotype less drastic than the typical phenotype attributed to classical lissencephaly. Therefore, the results described in the present manuscript corroborate the idea that mutations in some regions of the Lis1 gene can produce phenotypes more similar to those typically described in schizophrenic and autistic patients and animal models.This work was supported by the Spanish State Research Agency, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (Grant Numbers SEV-2017-0723), the Spanish Ministerio de Ciencia e Innovación grant numbers SAF2017-83702-R and PID2020-11817RB-I00, the Generalitat Valenciana (program Prometeo II, Grant Number 2018/041), and partly by the Israel Science Foundation: Israel Science Foundation (ISF)—National Natural Science Foundation of China (NSFC) (Grant No. 2449/16), Grant No. 2397/18 from the Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation.Peer reviewedFrontiers MediaMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Generalitat ValencianaIsrael Science FoundationNational Natural Science Foundation of ChinaCanadian Institutes of Health ResearchInternational Development Research Centre (Canada)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/286082reponame: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//SEV-2017-0723info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83702-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118171RB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.3389/fcell.2022.769853https://doi.org/10.3389/fcell.2022.769853Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2860822026-05-22T06:33:51Z
dc.title.none.fl_str_mv Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
title Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
spellingShingle Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
Domínguez-Sala, Eduardo
title_short Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
title_full Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
title_fullStr Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
title_full_unstemmed Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
title_sort Abnormalities in cortical GABAergic Interneurons of the primary motor cortex caused by Lis1 (Pafah1b1) mutation produce a non-drastic functional phenotype
dc.creator.none.fl_str_mv Domínguez-Sala, Eduardo
Valdés-Sánchez, María Lourdes
Canals, Santiago
Reiner, Orly
Pombero, Ana
García López, Raquel
Estirado, Alicia
Pastor, Diego
Geijo-Barrientos, Emilio
Martínez, Salvador
author Domínguez-Sala, Eduardo
author_facet Domínguez-Sala, Eduardo
Valdés-Sánchez, María Lourdes
Canals, Santiago
Reiner, Orly
Pombero, Ana
García López, Raquel
Estirado, Alicia
Pastor, Diego
Geijo-Barrientos, Emilio
Martínez, Salvador
author_role author
author2 Valdés-Sánchez, María Lourdes
Canals, Santiago
Reiner, Orly
Pombero, Ana
García López, Raquel
Estirado, Alicia
Pastor, Diego
Geijo-Barrientos, Emilio
Martínez, Salvador
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Generalitat Valenciana
Israel Science Foundation
National Natural Science Foundation of China
Canadian Institutes of Health Research
International Development Research Centre (Canada)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description LIS1 (PAFAH1B1) plays a major role in the developing cerebral cortex, and haploinsufficient mutations cause human lissencephaly type 1. We have studied morphological and functional properties of the cerebral cortex of mutant mice harboring a deletion in the first exon of the mouse Lis1 (Pafah1b1) gene, which encodes for the LisH domain. The Lis1/sLis1 animals had an overall unaltered cortical structure but showed an abnormal distribution of cortical GABAergic interneurons (those expressing calbindin, calretinin, or parvalbumin), which mainly accumulated in the deep neocortical layers. Interestingly, the study of the oscillatory activity revealed an apparent inability of the cortical circuits to produce correct activity patterns. Moreover, the fast spiking (FS) inhibitory GABAergic interneurons exhibited several abnormalities regarding the size of the action potentials, the threshold for spike firing, the time course of the action potential after-hyperpolarization (AHP), the firing frequency, and the frequency and peak amplitude of spontaneous excitatory postsynaptic currents (sEPSC’s). These morphological and functional alterations in the cortical inhibitory system characterize the Lis1/sLis1 mouse as a model of mild lissencephaly, showing a phenotype less drastic than the typical phenotype attributed to classical lissencephaly. Therefore, the results described in the present manuscript corroborate the idea that mutations in some regions of the Lis1 gene can produce phenotypes more similar to those typically described in schizophrenic and autistic patients and animal models.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
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/10261/286082
url http://hdl.handle.net/10261/286082
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI//SEV-2017-0723
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83702-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118171RB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.3389/fcell.2022.769853
https://doi.org/10.3389/fcell.2022.769853
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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
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