Entorhinal tau pathology disrupts hippocampal-prefrontal oscillatory coupling during associative learning

A neural signature of asymptomatic preclinical Alzheimer's disease (AD) is disrupted connectivity between brain regions; however, its underlying mechanisms remain unknown. Here, we tested whether a preclinical pathologic feature, tau aggregation in the entorhinal cortex (EC) is sufficient to disrupt the coordination of local field potentials (LFPs) between its efferent regions. P301L-mutant human tau or green fluorescent protein (GFP) was virally overexpressed in the EC of adult rats. LFPs were recorded from the dorsal hippocampus and prelimbic medial prefrontal cortex while the rats underwent trace eyeblink conditioning where they learned to associate 2 stimuli separated by a short time interval. In GFP-expressing rats, the 2 regions strengthened phase-phase and amplitude-amplitude couplings of theta and gamma oscillations during the interval separating the paired stimuli. Despite normal memory acquisition, this learning-related, inter-region oscillatory coupling was attenuated in the tau-expressing rats while prefrontal phase-amplitude theta-gamma cross-frequency coupling was elevated. Thus, EC tau aggregation caused aberrant long-range circuit activity during associative learning, identifying a culprit for the neural signature of preclinical AD stages.