Abstract
Network hyperexcitability is a feature of Alzheimer’s disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram activity from mice, and studied modulation by circadian cycle, behavioural, and brain state. We report that while J20s exhibit frequent inter-ictal spikes (IIS), APPNL/F mice do not. In J20 mice, IIS were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid-eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.
Significance Statement It is increasingly recognized that Alzheimer’s disease (AD) is associated with hyperexcitability in brain networks. Brain network hyperexcitability is also reported in several rodent models of AD. We studied the signatures of this hyperexcitability in two rodent models of AD as well as AD patients. Network hyperexcitability was prevalent in a transgenic model of AD, but was absent in a rodent model that is considered to be more physiologic. Moreover, while network hyperexcitability was coupled to rapid-eye movement (REM) sleep in transgenic mice, hyperexcitability occurred in non-REM sleep in AD patients. We suggest that brain state coupling of hyperexcitability can be used as a method for screening animal models of AD.
Footnotes
Authors declare no conflict of interest.
This work was supported by the grants awarded to IO from the following funders: the Alzheimer’s Society (PG-2012-208), the RS Macdonald Charitable Trust, The Muir Maxwell Epilepsy Centre, The Euan MacDonald Centre and The Patrick Wild Centre. ADL was supported by the American Academy of Neurology Institute. AGS was supported by Epilepsy Research UK. RC-CC was supported by an MRC grant (MR/M024075/1) awarded to RRR.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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