State-Dependent Alterations of Hippocampal Theta–Gamma Coupling in 5xFAD Mice and Their Differential Modulation by Donepezil

Background/Objectives: Alzheimer’s disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta–gamma coupling in 5xFAD mice across behavioral states and after donepezil. Methods: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta–gamma phase–amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil. Results: Untreated 5xFAD mice showed reduced theta–low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta–high-gamma coupling in all three contexts. Donepezil increased theta–low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta–high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta–high-gamma coupling correlated positively with open-field center time in WT mice only. Conclusions: Hippocampal theta–gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta–low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil’s effect on theta–high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.