---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '17293'
abstract:
- lang: eng
text: Voltage-gated CaV2.1 (P/Q-type) Ca2+ channels play a crucial role in regulating
neurotransmitter release, thus contributing to synaptic plasticity and to processes
such as learning and memory. Despite their recognized importance in neural function,
there is limited information on their potential involvement in neurodegenerative
conditions such as Alzheimer's disease (AD). Here, we aimed to explore the impact
of AD pathology on the density and nanoscale compartmentalization of CaV2.1 channels
in the hippocampus in association with GABAB receptors. Histoblotting experiments
showed that the density of CaV2.1 channel was significantly reduced in the hippocampus
of APP/PS1 mice in a laminar-dependent manner. CaV2.1 channel was enriched in
the active zone of the axon terminals and was present at a very low density over
the surface of dendritic tree of the CA1 pyramidal cells, as shown by quantitative
SDS-digested freeze-fracture replica labelling (SDS-FRL). In APP/PS1 mice, the
density of CaV2.1 channel in the active zone was significantly reduced in the
strata radiatum and lacunosum-moleculare, while it remained unaltered in the stratum
oriens. The decline in Cav2.1 channel density was found to be associated with
a corresponding impairment in the GABAergic synaptic function, as evidenced by
electrophysiological experiments carried out in the hippocampus of APP/PS1 mice.
Remarkably, double SDS-FRL showed a co-clustering of CaV2.1 channel and GABAB1
receptor in nanodomains (~40–50 nm) in wild type mice, while in APP/PS1 mice this
nanoarchitecture was absent. Together, these findings suggest that the AD pathology-induced
reduction in CaV2.1 channel density and CaV2.1-GABAB1 de-clustering may play a
role in the synaptic transmission alterations shown in the AD hippocampus. Therefore,
uncovering these layer-dependent changes in P/Q calcium currents associated with
AD pathology can benefit the development of future strategies for AD management.
acknowledgement: "Funding sources were Spanish Ministerio de Economía y Competitividad,
Junta de Comunidades de Castilla-La Mancha (Spain), Life Science Innovation Center
at University of Fukui and German Research Foundation.\r\nGrants RTI2018-095812-B-I00
and PID2021-125875OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A
way of making Europe” to Rafael Luján. This study was also supported by a grant
from Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229 and SBPLY/21/180501/000064)
and Universidad de Castilla-La Mancha (2023-GRIN-34187) to Rafael Luján, and Life
Science Innovation Center (Research and Education Program for Life Science) at University
of Fukui and JSPS KAKENHI Grant Numbers 16H04662, 17K19446, 18H05120 to Yugo Fukazawa
and Margarita Salas fellowship from Ministerio de Universidades and Universidad
de Castilla-La Mancha to Alejandro Martín-Belmonte. German Research Foundation (DFG
FOR 2143) and BIOSS-2 to Akos Kulik."
article_number: e13279
article_processing_charge: Yes
article_type: original
author:
- first_name: Alejandro
full_name: Martín‐Belmonte, Alejandro
last_name: Martín‐Belmonte
- first_name: Carolina
full_name: Aguado, Carolina
last_name: Aguado
- first_name: Rocío
full_name: Alfaro‐Ruiz, Rocío
last_name: Alfaro‐Ruiz
- first_name: Akos
full_name: Kulik, Akos
last_name: Kulik
- first_name: Luis
full_name: de la Ossa, Luis
last_name: de la Ossa
- first_name: Ana Esther
full_name: Moreno‐Martínez, Ana Esther
last_name: Moreno‐Martínez
- first_name: Samuel
full_name: Alberquilla, Samuel
last_name: Alberquilla
- first_name: Lucía
full_name: García‐Carracedo, Lucía
last_name: García‐Carracedo
- first_name: Miriam
full_name: Fernández, Miriam
last_name: Fernández
- first_name: Ana
full_name: Fajardo‐Serrano, Ana
last_name: Fajardo‐Serrano
- first_name: Ester
full_name: Aso, Ester
last_name: Aso
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: Eduardo D.
full_name: Martín, Eduardo D.
last_name: Martín
- first_name: Yugo
full_name: Fukazawa, Yugo
last_name: Fukazawa
- first_name: Francisco
full_name: Ciruela, Francisco
last_name: Ciruela
- first_name: Rafael
full_name: Luján, Rafael
last_name: Luján
citation:
ama: 'Martín‐Belmonte A, Aguado C, Alfaro‐Ruiz R, et al. Nanoarchitecture of CaV>2.1
channels and GABAB receptors in the mouse hippocampus: Impact of APP/PS1 pathology.
Brain Pathology. 2025;35(2). doi:10.1111/bpa.13279'
apa: 'Martín‐Belmonte, A., Aguado, C., Alfaro‐Ruiz, R., Kulik, A., de la Ossa, L.,
Moreno‐Martínez, A. E., … Luján, R. (2025). Nanoarchitecture of CaV>2.1 channels
and GABAB receptors in the mouse hippocampus: Impact of APP/PS1 pathology. Brain
Pathology. Wiley. https://doi.org/10.1111/bpa.13279'
chicago: 'Martín‐Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro‐Ruiz, Akos Kulik,
Luis de la Ossa, Ana Esther Moreno‐Martínez, Samuel Alberquilla, et al. “Nanoarchitecture
of CaV>2.1 Channels and GABAB Receptors in the Mouse Hippocampus: Impact of
APP/PS1 Pathology.” Brain Pathology. Wiley, 2025. https://doi.org/10.1111/bpa.13279.'
ieee: 'A. Martín‐Belmonte et al., “Nanoarchitecture of CaV>2.1 channels
and GABAB receptors in the mouse hippocampus: Impact of APP/PS1 pathology,” Brain
Pathology, vol. 35, no. 2. Wiley, 2025.'
ista: 'Martín‐Belmonte A, Aguado C, Alfaro‐Ruiz R, Kulik A, de la Ossa L, Moreno‐Martínez
AE, Alberquilla S, García‐Carracedo L, Fernández M, Fajardo‐Serrano A, Aso E,
Shigemoto R, Martín ED, Fukazawa Y, Ciruela F, Luján R. 2025. Nanoarchitecture
of CaV>2.1 channels and GABAB receptors in the mouse hippocampus: Impact of
APP/PS1 pathology. Brain Pathology. 35(2), e13279.'
mla: 'Martín‐Belmonte, Alejandro, et al. “Nanoarchitecture of CaV>2.1 Channels
and GABAB Receptors in the Mouse Hippocampus: Impact of APP/PS1 Pathology.” Brain
Pathology, vol. 35, no. 2, e13279, Wiley, 2025, doi:10.1111/bpa.13279.'
short: A. Martín‐Belmonte, C. Aguado, R. Alfaro‐Ruiz, A. Kulik, L. de la Ossa, A.E.
Moreno‐Martínez, S. Alberquilla, L. García‐Carracedo, M. Fernández, A. Fajardo‐Serrano,
E. Aso, R. Shigemoto, E.D. Martín, Y. Fukazawa, F. Ciruela, R. Luján, Brain Pathology
35 (2025).
date_created: 2024-07-22T07:48:20Z
date_published: 2025-03-01T00:00:00Z
date_updated: 2025-05-19T13:58:12Z
day: '01'
ddc:
- '570'
department:
- _id: RySh
doi: 10.1111/bpa.13279
external_id:
isi:
- '001250034200001'
pmid:
- '38887180'
file:
- access_level: open_access
checksum: 75a172800ab2e949abb66fba97cf70f0
content_type: application/pdf
creator: dernst
date_created: 2025-04-16T09:56:08Z
date_updated: 2025-04-16T09:56:08Z
file_id: '19582'
file_name: 2025_BrainPathology_MartinBelmonte.pdf
file_size: 8767863
relation: main_file
success: 1
file_date_updated: 2025-04-16T09:56:08Z
has_accepted_license: '1'
intvolume: ' 35'
isi: 1
issue: '2'
language:
- iso: eng
month: '03'
oa: 1
oa_version: Published Version
pmid: 1
publication: Brain Pathology
publication_identifier:
eissn:
- 1750-3639
issn:
- 1015-6305
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Nanoarchitecture of CaV>2.1 channels and GABAB receptors in the mouse hippocampus:
Impact of APP/PS1 pathology'
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
(CC BY-NC-ND 4.0)
short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 35
year: '2025'
...
---
_id: '7207'
abstract:
- lang: eng
text: The hippocampus plays key roles in learning and memory and is a main target
of Alzheimer's disease (AD), which causes progressive memory impairments. Despite
numerous investigations about the processes required for the normal hippocampal
functions, the neurotransmitter receptors involved in the synaptic deficits by
which AD disables the hippocampus are not yet characterized. By combining histoblots,
western blots, immunohistochemistry and high‐resolution immunoelectron microscopic
methods for GABAB receptors, this study provides a quantitative description of
the expression and the subcellular localization of GABAB1 in the hippocampus in
a mouse model of AD at 1, 6 and 12 months of age. Western blots and histoblots
showed that the total amount of protein and the laminar expression pattern of
GABAB1 were similar in APP/PS1 mice and in age‐matched wild‐type mice. In contrast,
immunoelectron microscopic techniques showed that the subcellular localization
of GABAB1 subunit did not change significantly in APP/PS1 mice at 1 month of age,
was significantly reduced in the stratum lacunosum‐moleculare of CA1 pyramidal
cells at 6 months of age and significantly reduced at the membrane surface of
CA1 pyramidal cells at 12 months of age. This reduction of plasma membrane GABAB1
was paralleled by a significant increase of the subunit at the intracellular sites.
We further observed a decrease of membrane‐targeted GABAB receptors in axon terminals
contacting CA1 pyramidal cells. Our data demonstrate compartment‐ and age‐dependent
reduction of plasma membrane‐targeted GABAB receptors in the CA1 region of the
hippocampus, suggesting that this decrease might be enough to alter the GABAB‐mediated
synaptic transmission taking place in AD.
article_processing_charge: No
article_type: original
author:
- first_name: Alejandro
full_name: Martín-Belmonte, Alejandro
last_name: Martín-Belmonte
- first_name: Carolina
full_name: Aguado, Carolina
last_name: Aguado
- first_name: Rocío
full_name: Alfaro-Ruíz, Rocío
last_name: Alfaro-Ruíz
- first_name: Ana Esther
full_name: Moreno-Martínez, Ana Esther
last_name: Moreno-Martínez
- first_name: Luis
full_name: De La Ossa, Luis
last_name: De La Ossa
- first_name: José
full_name: Martínez-Hernández, José
last_name: Martínez-Hernández
- first_name: Alain
full_name: Buisson, Alain
last_name: Buisson
- first_name: Simon
full_name: Früh, Simon
last_name: Früh
- first_name: Bernhard
full_name: Bettler, Bernhard
last_name: Bettler
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: Yugo
full_name: Fukazawa, Yugo
last_name: Fukazawa
- first_name: Rafael
full_name: Luján, Rafael
last_name: Luján
citation:
ama: Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, et al. Reduction in the neuronal
surface of post and presynaptic GABA>B< receptors in the hippocampus in
a mouse model of Alzheimer’s disease. Brain Pathology. 2020;30(3):554-575.
doi:10.1111/bpa.12802
apa: Martín-Belmonte, A., Aguado, C., Alfaro-Ruíz, R., Moreno-Martínez, A. E., De
La Ossa, L., Martínez-Hernández, J., … Luján, R. (2020). Reduction in the neuronal
surface of post and presynaptic GABA>B< receptors in the hippocampus in
a mouse model of Alzheimer’s disease. Brain Pathology. Wiley. https://doi.org/10.1111/bpa.12802
chicago: Martín-Belmonte, Alejandro, Carolina Aguado, Rocío Alfaro-Ruíz, Ana Esther
Moreno-Martínez, Luis De La Ossa, José Martínez-Hernández, Alain Buisson, et al.
“Reduction in the Neuronal Surface of Post and Presynaptic GABA>B< Receptors
in the Hippocampus in a Mouse Model of Alzheimer’s Disease.” Brain Pathology.
Wiley, 2020. https://doi.org/10.1111/bpa.12802.
ieee: A. Martín-Belmonte et al., “Reduction in the neuronal surface of post
and presynaptic GABA>B< receptors in the hippocampus in a mouse model
of Alzheimer’s disease,” Brain Pathology, vol. 30, no. 3. Wiley, pp. 554–575,
2020.
ista: Martín-Belmonte A, Aguado C, Alfaro-Ruíz R, Moreno-Martínez AE, De La Ossa
L, Martínez-Hernández J, Buisson A, Früh S, Bettler B, Shigemoto R, Fukazawa Y,
Luján R. 2020. Reduction in the neuronal surface of post and presynaptic GABA>B<
receptors in the hippocampus in a mouse model of Alzheimer’s disease. Brain Pathology.
30(3), 554–575.
mla: Martín-Belmonte, Alejandro, et al. “Reduction in the Neuronal Surface of Post
and Presynaptic GABA>B< Receptors in the Hippocampus in a Mouse Model
of Alzheimer’s Disease.” Brain Pathology, vol. 30, no. 3, Wiley, 2020,
pp. 554–75, doi:10.1111/bpa.12802.
short: A. Martín-Belmonte, C. Aguado, R. Alfaro-Ruíz, A.E. Moreno-Martínez, L. De
La Ossa, J. Martínez-Hernández, A. Buisson, S. Früh, B. Bettler, R. Shigemoto,
Y. Fukazawa, R. Luján, Brain Pathology 30 (2020) 554–575.
date_created: 2019-12-22T23:00:43Z
date_published: 2020-05-01T00:00:00Z
date_updated: 2025-07-10T11:54:22Z
day: '01'
ddc:
- '570'
department:
- _id: RySh
doi: 10.1111/bpa.12802
ec_funded: 1
external_id:
isi:
- '000502270900001'
pmid:
- '31729777'
file:
- access_level: open_access
checksum: 549cc1b18f638a21d17a939ba5563fa9
content_type: application/pdf
creator: dernst
date_created: 2020-09-22T09:47:19Z
date_updated: 2020-09-22T09:47:19Z
file_id: '8554'
file_name: 2020_BrainPathology_MartinBelmonte.pdf
file_size: 4220935
relation: main_file
success: 1
file_date_updated: 2020-09-22T09:47:19Z
has_accepted_license: '1'
intvolume: ' 30'
isi: 1
issue: '3'
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: 554-575
pmid: 1
project:
- _id: 25CBA828-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '720270'
name: Human Brain Project Specific Grant Agreement 1
- _id: 26436750-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '785907'
name: Human Brain Project Specific Grant Agreement 2
publication: Brain Pathology
publication_identifier:
eissn:
- 1750-3639
issn:
- 1015-6305
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: Reduction in the neuronal surface of post and presynaptic GABA>B< receptors
in the hippocampus in a mouse model of Alzheimer's disease
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 30
year: '2020'
...