Abstract
G protein-gated inwardly rectifying K+ (GIRK) channels are the main targets controlling excitability and synaptic plasticity on hippocampal neurons. Consequently, dysfunction of GIRK-mediated signalling has been implicated in the pathophysiology of Alzheimer´s disease (AD). Here, we provide a quantitative description on the expression and localisation patterns of GIRK2 in two transgenic mice models of AD (P301S and APP/PS1 mice), combining histoblots and immunoelectron microscopic approaches. The histoblot technique revealed differences in the expression of GIRK2 in the two transgenic mice models. The expression of GIRK2 was significantly reduced in the hippocampus of P301S mice in a laminar-specific manner at 10 months of age but was unaltered in APP/PS1 mice at 12 months compared to age-matched wild type mice. Ultrastructural approaches using the pre-embedding immunogold technique, demonstrated that the subcellular localisation of GIRK2 was significantly reduced along the neuronal surface of CA1 pyramidal cells, but increased in its frequency at cytoplasmic sites, in both P301S and APP/PS1 mice. We also found a decrease in plasma membrane GIRK2 channels in axon terminals contacting dendritic spines of CA1 pyramidal cells in P301S and APP/PS1 mice. These data demonstrate for the first time a redistribution of GIRK channels from the plasma membrane to intracellular sites in different compartments of CA1 pyramidal cells. Altogether, the pre- and post-synaptic reduction of GIRK2 channels suggest that GIRK-mediated alteration of the excitability in pyramidal cells could contribute to the cognitive dysfunctions as described in the two AD animal models.
Highlights
G protein-gated inwardly rectifying K+ (GIRK) channels are a family of ion channels functionally coupled to PTX-sensitive G protein-coupled receptors (GPCRs), which generate slow inhibitory postsynaptic potentials [1,2]
GIRK2 immunolabelling was widely distributed in the brain at the two ages studied, with strong labelling in the hippocampus, neocortex, cerebellum, septum, and thalamus (Figure 1A,C,D,F)
Given that GIRK channels play a crucial role in cognitive function [26], their pathophysiological alterations have been demonstrated in Alzheimer’s disease (AD) [21,27,28,29], highlighting their potential therapeutic applicability [9,12]
Summary
G protein-gated inwardly rectifying K+ (GIRK) channels are a family of ion channels functionally coupled to PTX-sensitive G protein-coupled receptors (GPCRs), which generate slow inhibitory postsynaptic potentials [1,2]. GIRK1, GIRK2, and GIRK3 are widely expressed in the CNS, whereas the expression of GIRK4 is generally lacking in the brain, with a few exceptions [14,15]. These subunits combine to form homomeric and heteromeric channels [16], the molecular diversity of neuronal GIRK channels resulting from their combination is limited. GIRK1 and GIRK2 can be co-immunoprecipitated, showed the same subcellular localisation patterns, and in regions where these subunits are co-expressed, the disruption of GIRK2 significantly reduces the expression of GIRK1 [10,18]
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