Low dose of a non-urea selective GIRK channel activator improves hippocampal-dependent synaptic plasticity and memory disrupted by amyloid-β oligomers

Abstract

Increased neural activity characterizes early Alzheimers disease (AD), serving as a prognostic indicator for disease progression and cognitive decline. Mechanisms that drive this hyperactivity and their behavioral effects remain mostly unrevealed, although normalizing altered excitability levels has been shown to reverse cognitive impairment in early AD, both in animals and humans. Soluble amyloid-{beta} oligomers (oA{beta}) primary accumulate in limbic regions like hippocampus and induce neuronal hyperexcitability and subsequent cognitive deficits by impairing ion channels function. Indeed, G protein-gated inwardly rectifying K+ (GIRK) channels -that control neuronal excitability-are greatly affected and their selective pharmacological activation has already been shown very effective to counteract oA{beta}-induced hyperexcitability and hippocampal dysfunction. However, GIRK gain-of-function in healthy animals disrupts learning, memory and underlying synaptic plasticity, greatly limiting its therapeutic potential in preclinical asymptomatic early 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 early oA{beta}1-42-generated AD male and female mice. Both doses normalized hippocampal synaptic plasticity (long-term potentiation, LTP) and associated spatial object location memory (OLM) without sex dimorphism in AD animals. However, in healthy mice, low VU0810464 dose did not significantly alter LTP and OLM, whereas the high dose disrupted both. 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.