Disruption of CaV 2.3 channels in the brain of the 5xFAD mice

Sep 29, 2026

CaV2.3 (R-type) channels mediate calcium signals that support neuronal excitability, synaptic plasticity, and neurotransmitter release in the hippocampus, yet their role in Alzheimer’s disease remains unclear. This study analyzes protein levels, expression, and subcellular localization of CaV2.3 in the hippocampus of 5xFAD mice using histoblot, western blot, qRT-PCR, and immunoelectron microscopy. Female mice show age- and lamina-dependent downregulation at 5 and 10 months, with hippocampus most affected and synaptic-layer changes. The reduced postsynaptic CaV2.3 may disrupt circuit activity and contribute to cognitive deficits.

LanguageEnglish

CategoryResearch & Report

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Pages19

Reading Time48 min

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Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Role of calcium and calcium dysregulation in AD

Voltage-gated Ca2+ channels and CaV2.3 features

Disruption of CaV 2.3 channels in the brain of the 5xFAD mice Carolina Aguado 1,2,* , Rocío Alfaro-Ruiz3,* , Alejandro Martín-Belmonte 1,2, Ricardo Puertas-Avendaño 1 , Miriam Fernández 1,2 , María Llanos Martínez-Poyato 1 , Eloy Portero-Campillo 1 , Miguel Pozuelo-Montero 1 , Ana Esther Moreno-Martínez 1,2, Pablo Alonso-Gómez 1, Akos Kulik4 and Rafael Luján 1,2 Journal of Alzheimer’s Disease 2026, Vol. 109(2) 699–717 © The Author(s) 2025 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/13872877251396963](DOI: 10.1177/13872877251396963)[ ](DOI: 10.1177/13872877251396963)[journals.sagepub.com/home/alz](journals.sagepub.com/home/alz) Abstract Background: CaV2.3 (R-type) channels mediate calcium signals involved in neuronal excitability, synaptic plasticity, and neurotransmitter release in the hippocampus. However, there is currently no information about their potential changes in Alzheimer’s disease (AD). Objective: This study aims to analyze the protein levels, expression, and subcellular localization of CaV2.3 channels in the hippocampus of 5xFAD mice. Methods: We employed histoblot, western blot, qRT-PCR, and immunoelectron microscopy techniques. Results: Using the histoblot technique, we observed that the protein content of CaV2.3 in female 5xFAD mice was downregulated in the hippocampus and caudate putamen at 5 months, with more pronounced downregulation at 10 months that also affected the septum. The hippocampus was the most affected region, where CaV2.3 immunodetection was signiﬁcantly decreased in a few dendritic layers at 5 months, but this reduction extended to all layers and subregions by 10 months, demonstrating age-and laminar-dependent changes. The pattern in females differed from that seen in males and remained unchanged in APP/PS1 and P301S mice. Immunoelectron microscopy of the hippocampus showed CaV2.3 in apical and oblique dendrites of CA1 pyramidal cells, with a signiﬁcantly higher presence in dendritic spines. Quantiﬁcation revealed a signiﬁcant decrease in the density of CaV2.3 in oblique dendrites and dendritic spines of CA1 pyramidal cells, whereas apical dendrites and presynaptic compartments were unaffected in 5xFAD mice. Conclusions: Overall, this downregulation in postsynaptic CaV2.3 channels could impact neural circuit activity and contribute to the cognitive deﬁcits observed in 5xFAD mice. Keywords Alzheimer’s disease, CaV2.3 channels, electron Received: 30 June 2025; accepted: 11 October 2025 microscopy, hippocampus, immunohistochemistry, 5xFAD 1 Synaptic Structure Laboratory, Instituto de Biomedicina de la UCLM (IB-UCLM), Departamento de Ciencias Médicas, Facultad de Medicina, Introduction Calcium (Ca2+) plays fundamental roles in different aspects of neuronal physiology, such as gene expression, neuronal growth, neuronal differentiation, synaptogenesis, membrane excitability, neurotransmitter release, synaptic plasticity, and learning and memory.1 Accordingly, disturbancesin Ca2+ homeostasis contribute to pathophysiological conditions, including Alzheimer’s disease (AD) .2,3 This neurodegenerative disease is characterized by three neuropathological hallmarks: extracellular deposition of amyloid-β (Aβ), intracellular neuroﬁbrillary tangles of tau, and loss of synapses.4 Changes in various Ca2+ channels, receptors, exchangers, and pumps have been shown to Universidad Castilla-La Mancha, Albacete, Spain 2Laboratorio de Estructura Sináptica, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Albacete, Spain 3Faculty of Health Sciences, Universidad Europea de Valencia, Valencia, Spain 4Institute for Physiology II, Medical Faculty, University of Freiburg, Freiburg, Germany *These authors contributed equally to this work. Corresponding author: Rafael Luján, Synaptic Structure Laboratory, Instituto de Biomedicina de la UCLM (IB-UCLM), De

FAQs

What is CaV2.3 (R-type) and what does it normally do in the hippocampus?

CaV2.3 channels mediate calcium signals involved in neuronal excitability, synaptic plasticity, and neurotransmitter release in the hippocampus.

How did the study assess changes in CaV2.3 channels in 5xFAD mice?

The study used histoblot, western blot, qRT-PCR, and immunoelectron microscopy to measure protein levels, expression, and subcellular localization.

What did the researchers find about CaV2.3 downregulation over age and brain region?

In female 5xFAD mice, CaV2.3 protein content was downregulated at 5 months and became more pronounced by 10 months, affecting additional regions including the septum, with the hippocampus showing strong laminar and subregion-dependent changes.

Sep 29, 2026

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