Authors :
Presenting Author: Manuel Silva-Pérez, PhD – Baylor College of Medicine
Jin Park, MSc – Baylor College of Medicine
Jeannie Chin, PhD – Baylor College of Medicine
Rationale:
Individuals with Alzheimer’s disease (AD) have an increased incidence of epileptiform activity, which may contribute to and accelerate cognitive decline. Seizures and epileptiform spikes occur primarily during sleep, particularly during nonrapid eye movement (NREM) sleep. Several transgenic mouse lines used to study AD-related neuropathology also exhibit epileptiform activity predominantly during sleep. However, these mice, many of which express human amyloid precursor protein (APP) carrying AD-linked mutations, tend to be studied quite early in disease progression before robust pathology is present and exhibit epileptiform spikes primarily during REM sleep rather than NREM sleep. In APP mice from line Tg2576, epileptiform spikes first emerge in REM sleep at very young ages and then propagate to NREM sleep at later timepoints, suggesting that the distribution of epileptiform activity across the sleep-wake states may shift with age and disease progression. Such an age- and disease-related shift in the occurrence of epileptiform activity has not been systematically studied; doing so could shed light on the mechanisms and evolution of epileptiform activity across AD progression.
Methods:
We carried out continuous video-EEG recordings in female and male APP mice from line J20 at 2, 13, 20, and 30 months of age. We quantified epileptiform spikes across the sleep-wake cycle as well as time spent in wakefulness, NREM sleep, and REM sleep. We also quantified sleep fragmentation, a prominent feature of AD.
Results:
In young mice in early stages of disease, epileptiform spikes were abundant during REM sleep, less frequent during NREM sleep and almost absent during wakefulness. Although REM sleep comprises less than 10% of total time of day in mice, over half of the total daily epileptiform spikes occurred during REM sleep. Notably, at later timepoints, the proportion of epileptiform spikes during NREM sleep steadily increased. Over 80% of total epileptiform spikes occurred during NREM sleep at 20 and 30 months of age. This shift was due to a gradual age-related decrease in the incidence of epileptiform spikes during REM sleep and an increase during NREM sleep. NREM sleep also became more fragmented with increasing age and disease-progression.Conclusions:
The incidence of epileptiform spikes shifts from occurring primarily during REM sleep to occurring predominantly during NREM sleep as APP mice age and disease progresses. The prevalence of epileptiform spikes in NREM sleep in aged APP mice better reflects what is observed in individuals with AD. Therefore, identifying the mechanisms that give rise to epileptiform spikes in APP mice, and underlie the shift from REM to NREM sleep, may provide novel insights into the basis of epileptiform activity in AD.
Funding:
Supported by a grant from the American Epilepsy Society (MSP) and grants NS085171 and AG065290 from the National Institutes of Health (JC).