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

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-beta (A beta) accumulation in the hippocampus during aging alters GIRK channel expression in mutant beta-amyloid precursor protein (APP(Sw,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 APP(Sw,Ind) J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APP(Sw,Ind) J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APP(Sw,Ind) J9 Ind mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APP(Sw,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.

Automated summary

This study investigates the impact of GIRK channel expression on transgenic mice models of Alzheimer's disease during aging. The findings suggest that GIRK2 may contribute to the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal-dependent task may reverse this effect.