Disruption of Ca2.3 channels in the brain of the 5xFAD mice.

Abstract

BackgroundCa2.3 (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).ObjectiveThis study aims to analyze the protein levels, expression, and subcellular localization of Ca2.3 channels in the hippocampus of 5xFAD mice.MethodsWe employed histoblot, western blot, qRT-PCR, and immunoelectron microscopy techniques.ResultsUsing the histoblot technique, we observed that the protein content of Ca2.3 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 Ca2.3 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 Ca2.3 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 Ca2.3 in oblique dendrites and dendritic spines of CA1 pyramidal cells, whereas apical dendrites and presynaptic compartments were unaffected in 5xFAD mice.ConclusionsOverall, this downregulation in postsynaptic Ca2.3 channels could impact neural circuit activity and contribute to the cognitive deficits observed in 5xFAD mice.