ML133

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction, with spatial memory impairments among the earliest detectable deficits. The dentate gyrus (DG), a critical region for spatial discrimination, exhibits functional alterations in patients with AD. Adult-born granule cells (abGCs) with higher intrinsic excitability are involved in DG-dependent spatial memory. However, it remains unclear the changes in intrinsic excitability of abGCs and underlying mechanisms at early stage of AD. In this study, 4-month-old APP/PS1 male mice exhibited spatial memory impairment and alterations in DG network activity. The inward rectifier K⁺ channel 2.1 (Kir 2.1) channels were upregulated in the hippocampus of the APP/PS1 mouse model of AD. Pharmacological inhibition of Kir 2.1 using ML133 significantly ameliorated spatial memory impairment and reversed the network activity of DG region. Whole-cell patch clamp recordings of 6-week-old abGCs revealed that intrinsic excitability was decreased in APP/PS1 mice relative to wild-type controls, which was attributable to excessive activation of Kir 2.1. These findings suggest that aberrant intrinsic excitability in the subgroup of abGCs may contribute to DG network activity alterations and induce spatial memory impairment. Our results identify Kir 2.1 overactivation in abGCs as a potential pathogenic mechanism and therapeutic target for early cognitive decline in early stage of AD.