VU0810464, a selective GIRK channel activator, improves hippocampal-dependent synaptic plasticity and memory disrupted by amyloid-β oligomers

-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.