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

Alzheimer's disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABA(B) receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on t...

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Autores: Martín Belmonte, Alejandro, Aguado, Carolina, Alfaro Ruiz, Rocío, Moreno Martínez, Ana Esther, De La Ossa, Luis, Aso Pérez, Ester, Gómez Acero, Laura, Shigemoto, Ryuichi, Fukazawa, Yugo, Ciruela Alférez, Francisco, Luján, Rafael
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/189968
Acesso em linha:https://hdl.handle.net/2445/189968
Access Level:acceso abierto
Palavra-chave:Hipocamp (Cervell)
Ratolins
Hippocampus (Brain)
Mice
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spelling Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 miceMartín Belmonte, AlejandroAguado, CarolinaAlfaro Ruiz, RocíoMoreno Martínez, Ana EstherDe La Ossa, LuisAso Pérez, EsterGómez Acero, LauraShigemoto, RyuichiFukazawa, YugoCiruela Alférez, FranciscoLuján, RafaelHipocamp (Cervell)RatolinsHippocampus (Brain)MiceAlzheimer's disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABA(B) 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-beta (A beta) pathology in GIRK channel density, subcellular distribution, and its association with GABA(B) 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 GABA(B1) 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, GABA(B1) and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABA(B1) 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 GABA(B) receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABA(B) receptor-GIRK channel membrane assembly causes dysregulation in the GABA(B) signalling via GIRK channels in this AD animal model.Springer Science and Business Media LLC2022202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion16 p.application/pdfhttps://hdl.handle.net/2445/189968Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s13195-022-01078-5Alzheimer's Research & Therapy, 2022, vol. 14, núm. 1https://doi.org/10.1186/s13195-022-01078-5cc by (c) Martín Belmonte, Alejandro et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1899682026-05-29T05:05:01Z
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
Hipocamp (Cervell)
Ratolins
Hippocampus (Brain)
Mice
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
Aguado, Carolina
Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
De La Ossa, Luis
Aso Pérez, Ester
Gómez Acero, Laura
Shigemoto, Ryuichi
Fukazawa, Yugo
Ciruela Alférez, Francisco
Luján, Rafael
author Martín Belmonte, Alejandro
author_facet Martín Belmonte, Alejandro
Aguado, Carolina
Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
De La Ossa, Luis
Aso Pérez, Ester
Gómez Acero, Laura
Shigemoto, Ryuichi
Fukazawa, Yugo
Ciruela Alférez, Francisco
Luján, Rafael
author_role author
author2 Aguado, Carolina
Alfaro Ruiz, Rocío
Moreno Martínez, Ana Esther
De La Ossa, Luis
Aso Pérez, Ester
Gómez Acero, Laura
Shigemoto, Ryuichi
Fukazawa, Yugo
Ciruela Alférez, Francisco
Luján, Rafael
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Hipocamp (Cervell)
Ratolins
Hippocampus (Brain)
Mice
topic Hipocamp (Cervell)
Ratolins
Hippocampus (Brain)
Mice
description Alzheimer's disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABA(B) 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-beta (A beta) pathology in GIRK channel density, subcellular distribution, and its association with GABA(B) 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 GABA(B1) 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, GABA(B1) and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABA(B1) 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 GABA(B) receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABA(B) receptor-GIRK channel membrane assembly causes dysregulation in the GABA(B) signalling via GIRK channels in this AD animal model.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/189968
url https://hdl.handle.net/2445/189968
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s13195-022-01078-5
Alzheimer's Research & Therapy, 2022, vol. 14, núm. 1
https://doi.org/10.1186/s13195-022-01078-5
dc.rights.none.fl_str_mv cc by (c) Martín Belmonte, Alejandro et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Martín Belmonte, Alejandro et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 16 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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