The Expression and Localisation of G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels Is Differentially Altered in the Hippocampus of Two Mouse Models of Alzheimer’s Disease

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.

Spatial memory training reverses GirK channels modulation in the transgenic APPSw,Ind Alzheimer’s disease mouse model

“…In agreement with our results, other authors have shown a reduction of GirK2 expression in the hippocampus of P301S mice, a murine model of tau pathology, yet no differences were found in APP/PS1 mice (Alfaro-Ruiz et al, 2021). This difference could be due to pathological and/or age differences between the models, since in the present study GirK2 down-expression was observed only at 6 months but not in older animals, as the ones used by Alfaro-Ruiz et al (2021). 10 On the other hand, no differences in the expression of any other GirK subunit were found due to genotype.…”

“…In fact, GIRK2 -/- mice showed elevated motor activity in an open field and elevated lever press behavior in an operant task (Pravetoni and Wickman, 2008), which show a hyperactivity in these mice that could be induced by the underlying neural hyperexcitability. In agreement with our results, other authors have shown a reduction of GirK2 expression in the hippocampus of P301S mice, a murine model of tau pathology, yet no differences were found in APP/PS1 mice (Alfaro-Ruiz et al, 2021). This difference could be due to pathological and/or age differences between the models, since in the present study GirK2 down-expression was observed only at 6 months but not in older animals, as the ones used by Alfaro-Ruiz et al (2021).…”

“…However, all this promising data have been obtained in an intracerebroventricular murine model of early AD, when Aβ is soluble rather than accumulated. A recent study has provided evidence of GirK redistribution from the plasma membrane to intracellular sites and pre- and post-synaptic reduction of GIRK2 channels in two transgenic AD models, P301S and APP/PS1 (Alfaro-Ruiz et al, 2021). Nevertheless, whether GirK subunits levels are altered in the brain of mice developing AD pathological changes during aging is unknown.…”

AsKC11, a Kunitz Peptide from Anemonia sulcata, Is a Novel Activator of G Protein-Coupled Inward-Rectifier Potassium Channels

“…The mammalian GIRK family is composed of four domains (GIRK1, GIRK2, GIRK3, and GIRK4 channels) encoded by KCNJ3, KCNJ6, KCNJ9, and KCNJ5 genes, respectively [9]. Among them, GIRK1, GIRK2, and GIRK3 channels are expressed in the brain and form either homotetramers of GIRK2 channel or heterotetramers (e.g., GIRK1/2 channels) in various brain regions with a high presence in the olfactory bulb, hippocampus, cortex, thalamus, and cerebellum, as well as in the spinal cord [1,5].…”

“…Among them, GIRK1, GIRK2, and GIRK3 channels are expressed in the brain and form either homotetramers of GIRK2 channel or heterotetramers (e.g., GIRK1/2 channels) in various brain regions with a high presence in the olfactory bulb, hippocampus, cortex, thalamus, and cerebellum, as well as in the spinal cord [1,5]. The prototypical functional form of GIRK channels in the brain consists primarily of heterotetrameric GIRK1/2 channels [5,9]. They control neuronal excitability and neurotransmission, confer bistability (transition from asynchronous spikes to synchronous bursts of activity) to neural networks [1].…”