MODULATION OF GIRK CHANNELS ACTIVITY IMPROVES HIPPOCAMPAL FUNCTION AND PARIETAL CORTEX NETWORK COHERENCE IN EARLY ALZHEIMER’S DISEASE IN MALE AND FEMALE MICE

Metaplasticity describes how previous synaptic activity can “prime” the capacity of synapses to undergo future plastic changes. In early Alzheimer’s disease (AD), soluble β-amyloid oligomers (oAβ) accumulate in limbic areas like the hippocampus, promoting neuronal hyperexcitability, acting as aberrant metaplastic phenomenon that contributes to cognitive decline. Targeting ion channels that regulate excitability, such as G–protein–gated inwardly rectifying K⁺ (GIRK) channels, has emerged as a promising strategy to preventively stabilize excitatory/inhibitory balance and counteract oAβ-induced dysfunction.
Here, we investigated whether GIRK priming could modulate metaplasticity and prevent early hippocampal impairments in a mouse model of AD-like pathology induced by oAβ_1-42 intracerebroventricular injection. Both male and female mice received a neuron-specific GIRK modulator prior to oAβ exposure. Ex vivo hippocampal electrophysiology, in vivo CA1 and parietal cortex oscillatory recordings, and spatial memory tasks, showed oAβ to impair synaptic metaplasticity, disrupt hippocampal-parietal cortical coherence and compromise cognitive performance. However, GIRK modulation before oAβ administration preserved hippocampal synaptic function, its network synchrony with parietal cortex and memory in both sexes.
In this context, GIRK modulation metaplastically tunes neuronal excitability prior to amyloid exposure, thereby overcoming aberrant metaplasticity. By stabilizing excitatory/inhibitory balance and preserving large-scale network dynamics, this approach may offer an avenue for delaying disease onset and progression. Its efficacy across sexes underscores its translational potential for broad therapeutic application.
MCIN/AEI/10.13039/501100011033(PID2020-115823-GBI00;PID2024-155413NB-I00), JCCM/FEDER(SBPLY/21/180501/000150;SBPLY/24/180225/000181), UCLM/FEDER(2022-GRIN-34354;2025-GRIN-38530) to JDNL/LJD.