Hippocampal and cortical activities reflect early hyperexcitability in an Alzheimer's mouse model

Abstract

Early stages of Alzheimer's disease are marked by brain hyperexcitability, evidenced by subclinical epileptiform features suggesting an excitation-inhibition imbalance. Clinically translatable biomarkers for early detection of excitation-inhibition changes at the network level, however, are lacking. We investigated the functional excitation-inhibition ratio, theta-gamma phase-amplitude coupling and epileptiform features in hippocampal and cortical local field potentials recorded weekly in freely behaving male APPswe/PS1dE9 (APP/PS1) mice (n = 10) and wild-type controls (n = 10) between 3 and up to and including 11 months of age. APP/PS1 mice exhibited a shift towards increased excitation, reflected in the elevated functional excitation-inhibition ratio emerging most prominently in the hippocampus at 6 months. Additionally, elevated population spiking activity and age-related impairments in theta-gamma phase-amplitude coupling were observed in the local field potentials of APP/PS1 mice in both the hippocampus and the cortex. Importantly, the functional excitation-inhibition ratio correlated positively with elevated population spiking activity in both brain regions in APP/PS1 mice. Our findings highlight the functional excitation-inhibition ratio as a promising biomarker of hippocampal and cortical network disinhibition and hyperexcitability in APP/PS1 mice, with potential value as an early disease marker in Alzheimer's disease.