Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice

Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribut...

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Autores: Alfaro-Ruiz, Rocio, Aguado, Carolina, Martín-Belmonte, Alejandro, Moreno-Martínez, Ana Esther, Merchán-Rubira, Jesús, Hernández, Félix, Ávila, Jesús, Fukazawa, Yugo, Luján, Rafael
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367172
Acesso em linha:http://hdl.handle.net/10261/367172
Access Level:acceso abierto
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spelling Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic MiceAlfaro-Ruiz, RocioAguado, CarolinaMartín-Belmonte, AlejandroMoreno-Martínez, Ana EstherMerchán-Rubira, JesúsHernández, FélixÁvila, JesúsFukazawa, YugoLuján, RafaelTau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD.This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (RTI2018-095812-B-I00 and PID2020-118511RB-I00) and Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229 and SBPLY/21/180501/000064) to RL, Life Science Innovation Center at University of Fukui and JSPS KAKENHI Grant Numbers 16H04662, 19H03323 and 20H05058) to YF, and Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha to AMB.Molecular Diversity Preservation InternationalMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Junta de Comunidades de Castilla-La ManchaUniversidad de Castilla La ManchaMinisterio de Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420222024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/367172reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#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/RTI2018-095812-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118511RB-I00http://dx.doi.org/10.3390/ijms232113527Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3671722026-05-22T06:33:51Z
dc.title.none.fl_str_mv Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
title Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
spellingShingle Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
Alfaro-Ruiz, Rocio
title_short Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
title_full Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
title_fullStr Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
title_full_unstemmed Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
title_sort Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice
dc.creator.none.fl_str_mv Alfaro-Ruiz, Rocio
Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán-Rubira, Jesús
Hernández, Félix
Ávila, Jesús
Fukazawa, Yugo
Luján, Rafael
author Alfaro-Ruiz, Rocio
author_facet Alfaro-Ruiz, Rocio
Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán-Rubira, Jesús
Hernández, Félix
Ávila, Jesús
Fukazawa, Yugo
Luján, Rafael
author_role author
author2 Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán-Rubira, Jesús
Hernández, Félix
Ávila, Jesús
Fukazawa, Yugo
Luján, Rafael
author2_role 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)
Junta de Comunidades de Castilla-La Mancha
Universidad de Castilla La Mancha
Ministerio de Universidades (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
2024
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/10261/367172
url http://hdl.handle.net/10261/367172
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#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095812-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-118511RB-I00
http://dx.doi.org/10.3390/ijms232113527
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
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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repository.mail.fl_str_mv
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