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

Area of Science:

• Neuroscience
• Pharmacology
• Alzheimer's Disease Research

Background:

• G protein-gated inwardly rectifying K+ (GIRK) channels regulate neuronal excitability and are targets for Alzheimer's disease (AD) therapy.
• Activating GIRK channels can counteract amyloid-β oligomer (oAβ)-induced hyperexcitability in early AD, but excessive activation impairs cognitive functions in healthy individuals.

Purpose of the Study:

• To evaluate the efficacy and safety of a novel, potent, and selective GIRK activator, VU0810464, in preclinical models of AD.
• To determine the dose-dependent effects of VU0810464 on synaptic plasticity and memory in both healthy and oAβ-induced AD-like mice, across sexes.

Main Methods:

• Administered two doses of VU0810464 to healthy and oAβ-infused mice (male and female).
• Assessed synaptic plasticity using CA3-CA1 long-term potentiation (LTP) in hippocampal slices.
• Evaluated hippocampal-dependent memory using the object location memory (OLM) task.
• Measured hippocampal network excitability.

Main Results:

• Both doses of VU0810464 normalized oAβ-induced deficits in hippocampal LTP and OLM.
• In healthy mice, a low dose of VU0810464 had no significant effect, while a higher dose impaired LTP and OLM.
• VU0810464 reduced oAβ-induced hippocampal hyperexcitability, demonstrating a link between GIRK activation and network excitability restoration.
• No significant sex differences were observed in any experimental condition.

Conclusions:

• Precise, low-dose tuning of neural excitability with VU0810464 may offer a safe strategy for treating early, preclinical AD.
• This approach could prevent hippocampal overexcitation and memory deficits associated with early-stage Alzheimer's disease.