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

HighlightsWhat are the main findings?5xFAD mice show reduced hippocampal theta–low gamma coupling and elevated theta–high gamma coupling.Donepezil preferentially enhances theta–low gamma coupling, with limited normalization of theta–high gamma coupling.What are the implications of the main findings?Theta–low gamma coupling may serve as a treatment-responsive readout of cholinergic modulation in AD models.Persistent theta–high gamma elevation may reflect a stable AD-related hippocampal network abnormality.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.