Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

Akyüz, Enes; Clara, Villa; Beker, Merve; Elibol, Birsen

doi:10.3390/biomedicines8030058

Cited by 8 publications

(5 citation statements)

References 26 publications

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“…In the present study, a decrease in GIRK2 protein expression was not detected in the hippocampus of APP/PS1 mice, consistent with the unaltered mRNA and protein expression of GIRK1 Aβ (1–42)-infused rat model of AD [ 38 ]. However, previous studies using different models showed that Aβ induces a reduction in gene expression of hippocampal GIRK channel subunits and decreases GIRK conductance in pyramidal cells [ 21 , 22 ] and a reduction of protein expression in the human hippocampus of AD [ 27 ].…”

Section: Discussionsupporting

confidence: 89%

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

Alfaro-Ruiz

Martín-Belmonte

Aguado

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 89%

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

Alfaro-Ruiz

Martín-Belmonte

Aguado

et al. 2021

IJMS

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“…On the other hand, no differences in the expression of any other GirK subunit were found due to genotype. Indeed, it has already been reported that amyloidosis did not affect the expression of GirK1 (Sánchez-Rodríguez et al, 2019a; Akyuz et al, 2020). Available data regarding GirK3 is limited, however, previous work from our group showed a decreased in the genetic expression of this subunit (Mayordomo-Cava et al, 2015), while present results revealed no genotype effect.…”

Section: Discussionmentioning

confidence: 90%

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

Temprano‐Carazo

Contreras

Saura

et al. 2022

Preprint

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Alzheimer’s disease (AD) is a dementia characterized by progressive memory decline and neurodegeneration caused by the accumulation of amyloid-β (Aβ) peptides. Last findings point to an imbalance between excitatory and inhibitory neurotransmission as the initial impairment in early stages, and the hippocampus as one of the most susceptible brain areas.The G-protein-gated inwardly rectifying potassium (GirK) channel has been proposed as a potential target to restore excitatory/inhibitory balance in amyloidosis models. Moreover, cognitive training may counteract early AD symptoms, although its effect on GirK channels remains unknown.Here, the effect of genotype, age, and training in a hippocampal-dependent memory task on the protein expression of GirK subunits and modulators were studied using APPSw,Ind mice. Results showed a reduction of GirK2 expression as well as an increased expression of SNX27 in the hippocampus of 6-month-old APPSw,Ind mice. Training in a memory task restored GirK2 and SNX27 levels. Thus, the effect of Aβ on GirK2 could account for the excitatory/inhibitory imbalance transmission found in AD models, and training in a cognitive hippocampal-dependent task reverses this effect and lessens early Aβ-dependent AD deficits.Summary statementAβ decreases hippocampal GirK2 expression in APPSw,Ind mice, which could contribute to early hyperexcitability found in Alzheimer’s disease models. Training in spatial memory tasks has shown to counteract this reduction.

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“…On the other hand, no differences in the expression of any other GIRK subunit were found due to hippocampal accumulation of Aβ (i.e., genotype). Indeed, it has already been reported that amyloidosis did not affect the expression of GIRK1 [ 23 , 36 ]. Available data regarding GIRK3 is limited, however, previous work from our group showed a decrease in gene expression of this subunit induced by soluble Aβ 25–35 [ 20 ], while present results revealed no genotype effect.…”

Section: Discussionmentioning

confidence: 99%

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer’s Disease Mouse Model

Temprano‐Carazo

Contreras

Saura

et al. 2022

IJMS

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G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of Alzheimer’s disease (AD) is largely unknown. Here, we study whether progressive amyloid-β (Aβ) accumulation in the hippocampus during aging alters GIRK channel expression in mutant β-amyloid precursor protein (APPSw,Ind J9) transgenic AD mice. Additionally, we examine the impact of spatial memory training in a hippocampal-dependent task, on protein expression of GIRK subunits and Regulator of G-protein signaling 7 (RGS7) in the hippocampus of APPSw,Ind J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APPSw,Ind J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APPSw,Ind J9 mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APPSw,Ind J9 mice were normalized to WT levels. Together, our results support the evidence that GIRK2 could account for the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal dependent task may have therapeutic benefits of reversing this effect and lessen early AD deficits.

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Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

Cited by 8 publications

References 26 publications

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

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

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

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer’s Disease Mouse Model

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Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

Cited by 8 publications

References 26 publications

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

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

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

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer’s Disease Mouse Model

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