Abstract

ObjectiveTo test the hypothesis that high frequency oscillations (HFOs) between 250 and 500Hz occur in mouse models of Alzheimers disease (AD) and thus are not unique to epilepsy. MethodsExperiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock-out (PS2KO) mice, and the Ts65Dn model of Downs syndrome. We recorded HFOs using wideband (0.1-500Hz, 2kHz) intra-hippocampal and cortical surface EEG at 1month until 24months-old during wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Interictal spikes (IIS) and seizures were also analyzed for the possible presence of HFOs. Comparisons were made to the intra-hippocampal kainic acid and pilocarpine models of epilepsy. ResultsWe describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1month of age and prior to amyloid-{beta} plaque neuropathology. HFOs were most frequent during SWS (vs. REM or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IIS and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. SignificanceOur data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker which is detectable from the scalp and thus amenable to non-invasive detection in people at risk for AD. KEY POINTSO_LIHigh frequency oscillations (HFOs, 250-500Hz) occur in mouse models of Alzheimers disease C_LIO_LIHFOs are detectable from the hippocampus and overlying cortex C_LIO_LIHFOs are most frequent during slow wave sleep C_LIO_LIHFOs in AD mouse models resemble HFOs in two animal models of epilepsy C_LIO_LIHFOs can be detected during interictal spikes and seizures in the AD models C_LI