Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice

Alzheimers disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippo...

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Autores: Martín Belmonte, Alejandro, Alfaro Ruiz, Rocío, Moreno Martínez, Ana Esther, Aso , Ester, Gómez Acero, Laura, Shigemoto , Ryuichi, Fukazawa , Yugo, Ciruela , Francisco, Aguado Rubio, Carolina, Ossa Jiménez, Luis de la, Luján Miras, Rafael
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad de Castilla-La Mancha
Repositorio:RUIdeRA. Repositorio Institucional de la UCLM
OAI Identifier:oai:ruidera.uclm.es:10578/40624
Acceso en línea:https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01078-5#availability-of-data-and-materials
https://hdl.handle.net/10578/40624
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
Cell surface density
Hippocampus
Metaboropic GABAb receptor
Nanodomains
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spelling Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 miceMartín Belmonte, AlejandroAlfaro Ruiz, RocíoMoreno Martínez, Ana EstherAso , EsterGómez Acero, LauraShigemoto , RyuichiFukazawa , YugoCiruela , FranciscoAguado Rubio, CarolinaOssa Jiménez, Luis de laLuján Miras, RafaelAlzheimer’s diseaseCell surface densityHippocampusMetaboropic GABAb receptorNanodomainsAlzheimers disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-ß (Aß) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model.Biomed Central - Springer Nature202520252022info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://alzres.biomedcentral.com/articles/10.1186/s13195-022-01078-5#availability-of-data-and-materialshttps://hdl.handle.net/10578/40624reponame:RUIdeRA. Repositorio Institucional de la UCLMinstname:Universidad de Castilla-La ManchaInglésinfo:eu-repo/semantics/openAccessoai:ruidera.uclm.es:10578/406242026-05-27T07:36:41Z
dc.title.none.fl_str_mv Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
title Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
spellingShingle Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
Martín Belmonte, Alejandro
Alzheimer’s disease
Cell surface density
Hippocampus
Metaboropic GABAb receptor
Nanodomains
title_short Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
title_full Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
title_fullStr Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
title_full_unstemmed Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
title_sort Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice
dc.creator.none.fl_str_mv Martín Belmonte, Alejandro
Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
Aso , Ester
Gómez Acero, Laura
Shigemoto , Ryuichi
Fukazawa , Yugo
Ciruela , Francisco
Aguado Rubio, Carolina
Ossa Jiménez, Luis de la
Luján Miras, Rafael
author Martín Belmonte, Alejandro
author_facet Martín Belmonte, Alejandro
Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
Aso , Ester
Gómez Acero, Laura
Shigemoto , Ryuichi
Fukazawa , Yugo
Ciruela , Francisco
Aguado Rubio, Carolina
Ossa Jiménez, Luis de la
Luján Miras, Rafael
author_role author
author2 Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
Aso , Ester
Gómez Acero, Laura
Shigemoto , Ryuichi
Fukazawa , Yugo
Ciruela , Francisco
Aguado Rubio, Carolina
Ossa Jiménez, Luis de la
Luján Miras, Rafael
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer’s disease
Cell surface density
Hippocampus
Metaboropic GABAb receptor
Nanodomains
topic Alzheimer’s disease
Cell surface density
Hippocampus
Metaboropic GABAb receptor
Nanodomains
description Alzheimers disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-ß (Aß) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model.
publishDate 2022
dc.date.none.fl_str_mv 2022
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01078-5#availability-of-data-and-materials
https://hdl.handle.net/10578/40624
url https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01078-5#availability-of-data-and-materials
https://hdl.handle.net/10578/40624
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Biomed Central - Springer Nature
publisher.none.fl_str_mv Biomed Central - Springer Nature
dc.source.none.fl_str_mv reponame:RUIdeRA. Repositorio Institucional de la UCLM
instname:Universidad de Castilla-La Mancha
instname_str Universidad de Castilla-La Mancha
reponame_str RUIdeRA. Repositorio Institucional de la UCLM
collection RUIdeRA. Repositorio Institucional de la UCLM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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