Abstract
Selective pharmacological activation of G protein-gated inwardly rectifying K⁺ (GIRK) channels -a key physiological determinant of neuronal excitability control- has proven highly effective in counteracting amyloid-β oligomer (oAβ)-induced hyperexcitability and hippocampal dysfunction in early Alzheimer's disease (AD). However, GIRK gain-of-function in healthy animals disrupts learning, memory and underlying synaptic plasticity, greatly limiting its therapeutic potential in preclinical asymptomatic AD patients. Therefore, GIRK-based pharmacological treatment needs further investigation to overcome these limitations. Here we tested two doses of a novel, more potent, and neuronal selective GIRK activator, VU0810464, in healthy and intracerebroventricular (icv.) oAβ1-42-induced AD-like male and female mice. Both doses normalized: 1) at the synaptic level, CA3-CA1 long-term synaptic potentiation (LTP) in hippocampal slices, and 2) at the behavioral level, object location memory (OLM), a hippocampal-dependent spatial contextual recognition memory task. However, in healthy mice, while a low VU0810464 dose had no significant effect on hippocampal LTP and OLM, the higher dose impaired both processes. Importantly, these effects were consistent across sexes, as no sex differences were observed in any condition. Finally, VU0810464 reduced oAβ-induced hippocampal hyperexcitability, providing direct functional evidence of a mechanistic link between GIRK activation and restoration of network excitability. Our results suggest that the precise tuning of neural excitability with low dosing of VU0810464 might be a promising strategy to safely treat and prevent hippocampal overexcitation and upstreaming memory deficits in early preclinical asymptomatic phases of AD.
