Disruption of hippocampal neuronal circuit function depends upon behavioral state in the APP/PS1 mouse model of Alzheimer's disease.

The Alzheimer's disease-associated peptide amyloid-beta (Aβ) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aβ, here we show that Aβ aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aβ impaired hippocampal theta-gamma phase-amplitude coupling and altered neuronal synchronization with theta.