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, Rocío, Aguado, Carolina, Martín-Belmonte, Alejandro, Moreno-Martínez, Ana Esther, Merchán Rubira, Jesús, Hernández Pérez, Félix, Ávila, Jesús, Fukazawa, Yasushi, Luján, Rafael
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/707343
Acceso en línea:http://hdl.handle.net/10486/707343
https://dx.doi.org/10.3390/ijms232113527
Access Level:acceso abierto
Palabra clave:Cell Density
Cellular Distribution
Molecular Pathology
Thalamus
Transgenic Mouse
Biología y Biomedicina / Biología
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spelling Alteration in the synaptic and extrasynaptic organization of AMPA receptors in the hippocampus of P301S tau transgenic miceAlfaro-Ruiz, RocíoAguado, CarolinaMartín-Belmonte, AlejandroMoreno-Martínez, Ana EstherMerchán Rubira, JesúsHernández Pérez, FélixÁvila, JesúsFukazawa, YasushiLuján, RafaelCell DensityCellular DistributionMolecular PathologyThalamusTransgenic MouseBiología y Biomedicina / BiologíaTau 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 ADThis 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 AMBMDPIDepartamento de Biología MolecularFacultad de Ciencias20222022-11-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/707343https://dx.doi.org/10.3390/ijms232113527reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7073432026-06-23T12:46:27Z
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, Rocío
Cell Density
Cellular Distribution
Molecular Pathology
Thalamus
Transgenic Mouse
Biología y Biomedicina / Biología
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, Rocío
Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán Rubira, Jesús
Hernández Pérez, Félix
Ávila, Jesús
Fukazawa, Yasushi
Luján, Rafael
author Alfaro-Ruiz, Rocío
author_facet Alfaro-Ruiz, Rocío
Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán Rubira, Jesús
Hernández Pérez, Félix
Ávila, Jesús
Fukazawa, Yasushi
Luján, Rafael
author_role author
author2 Aguado, Carolina
Martín-Belmonte, Alejandro
Moreno-Martínez, Ana Esther
Merchán Rubira, Jesús
Hernández Pérez, Félix
Ávila, Jesús
Fukazawa, Yasushi
Luján, Rafael
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biología Molecular
Facultad de Ciencias
dc.subject.none.fl_str_mv Cell Density
Cellular Distribution
Molecular Pathology
Thalamus
Transgenic Mouse
Biología y Biomedicina / Biología
topic Cell Density
Cellular Distribution
Molecular Pathology
Thalamus
Transgenic Mouse
Biología y Biomedicina / Biología
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
2022-11-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/707343
https://dx.doi.org/10.3390/ijms232113527
url http://hdl.handle.net/10486/707343
https://dx.doi.org/10.3390/ijms232113527
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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