NORMALIZING NEURAL EXCITABILITY IN EARLY ALZHEIMER’S DISEASE COUNTERACTS GLIAL REACTIVITY INDUCED BY AMYLOID-Β OLIGOMERS IN MALE AND FEMALE MICE

In early Alzheimer’s disease (AD), soluble amyloid-β oligomers (oAβ) accumulate in limbic regions like hippocampus promoting neuronal hyperexcitability and neuroinflammation that precede neuronal loss and cognitive decline. Normalizing neural excitability through G protein-gated inwardly rectifying K⁺ (GIRK) channels activation has been shown to improve hippocampal-dependent synaptic plasticity and memory disrupted by oAβ. Although astrocytes and microglia have been shown to be essential for maintaining these functions, the effects of oAβ-induced hyperexcitability on their temporal activation remain poorly understood.
To address this, male and female mice of a non-transgenic model of acute hippocampal amyloidosis induced by intracerebroventricular (icv.) injection of oAβ_1-42 were used. Glial reactivity was evaluated at 1, 24, and 48h post-injection using immunohistochemistry and WB analysis of GFAP and Iba-1. Astrogliosis and microgliosis were detected at all-time points, with time/cell type dependent sex-dimorphism. Additionally, astrocytic Sholl analysis showed marked hypertrophy and increased morphological complexity as early as 1h, persisting up to 24h.
Then, 24h post-oAβ injection, a selective GIRK activator was icv-injected to assess its effect on astrocytic reactivity. Notably, GIRK channel activation significantly reduced astrocytic reactivity at 24h, by decreasing GFAP levels. However, whole cell patch-clamp recordings obtained from astrocytes cultures showed no significant changes in membrane conductance when potential was clamped at -70mV.
Together, these findings demonstrate that hyperexcitability induced by oAβ_1-42 produces rapid and sustained glial activation and identify neuronal GIRK channel activation as a potential strategy to modulate astrocytic reactivity by normalizing hyperexcitability during early amyloidosis.
Acknowledgements: 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.