Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features

The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germ...

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Autores: Aller, María Isabel, Pecoraro, Valeria, Paternain, Ana V., Canals, Santiago, Lerma Gómez, Juan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/308447
Acceso en línea:http://hdl.handle.net/10261/308447
Access Level:acceso abierto
Palabra clave:Anxiety
Autism
Depression
GluK4
Grik4
High-affinity kainate receptor
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spelling Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders featuresAller, María IsabelPecoraro, ValeriaPaternain, Ana V.Canals, SantiagoLerma Gómez, JuanAnxietyAutismDepressionGluK4Grik4High-affinity kainate receptorThe understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders.This work was supported by grants to J.L. from the Spanish Ministry of Science and Innovation (BFU2011-24084), Consolider (CSD2007-00023) Generalitat Valenciana GVPRE/2008/023, Prometeo/2011/086, and PrometeoII/2015/012. The Santiago Grisolia fellowship program from the Generalitat Valenciana supports V.P. The Instituto de Neurociencias is a Centre of Excellence Severo Ochoa.Peer reviewedSociety for NeuroscienceMinisterio de Ciencia e Innovación (España)Generalitat ValencianaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/308447reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MICINN//BFU2011-24084Journal of Neurosciencehttps://doi.org/10.1523/JNEUROSCI.2217-15.2015Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3084472026-05-22T06:33:51Z
dc.title.none.fl_str_mv Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
title Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
spellingShingle Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
Aller, María Isabel
Anxiety
Autism
Depression
GluK4
Grik4
High-affinity kainate receptor
title_short Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
title_full Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
title_fullStr Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
title_full_unstemmed Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
title_sort Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features
dc.creator.none.fl_str_mv Aller, María Isabel
Pecoraro, Valeria
Paternain, Ana V.
Canals, Santiago
Lerma Gómez, Juan
author Aller, María Isabel
author_facet Aller, María Isabel
Pecoraro, Valeria
Paternain, Ana V.
Canals, Santiago
Lerma Gómez, Juan
author_role author
author2 Pecoraro, Valeria
Paternain, Ana V.
Canals, Santiago
Lerma Gómez, Juan
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Generalitat Valenciana
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Anxiety
Autism
Depression
GluK4
Grik4
High-affinity kainate receptor
topic Anxiety
Autism
Depression
GluK4
Grik4
High-affinity kainate receptor
description The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders.
publishDate 2015
dc.date.none.fl_str_mv 2015
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/10261/308447
url http://hdl.handle.net/10261/308447
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/MICINN//BFU2011-24084
Journal of Neuroscience
https://doi.org/10.1523/JNEUROSCI.2217-15.2015
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 Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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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