On neuronal hyperexcitability in a mouse model of B-amyloid neuropathology

At present, Alzheimer’s disease (AD) is an incurable neurodegenerative dementia. It has been suggested that neuronal hyperexcitability contributes to AD, so we asked how hyperexcitability develops in a common mouse model of β-amyloid neuropathology - Tg2576 mice. These mice overexpress the Swedish familial mutation of human-amyloid precursor protein (hAPP). Using video-EEG recordings, we found synchronized, large amplitude potentials resembling interictal spikes (IIS) in epilepsy at just 5 weeks of age, long before memory impairments or β-amyloid deposition. Seizures were uncommon, but occurred later in life, suggesting that IIS are possibly the earliest form of hyperexcitability. Interestingly, IIS primarily occurred during rapid-eye movement (REM) sleep prior to the deposition of β-amyloid. The interests are twofold. First, REM sleep is associated with increased cholinergic tone. Second, cholinergic impairments as well as degeneration are implicated in AD. Although previous studies suggest that cholinergic antagonists would worsen pathophysiology, the muscarinic antagonist atropine but not nicotinic antagonists reduced IIS frequency in animals prior to β-amyloid deposition. In addition, we found a role for brain hyperexcitability during general anesthesia. Epileptiform discharges are both hyperexcitable and hypersynchronous across age in Tg2576 mice and wildtypes. Our findings identify that epileptiform discharges elicited during anesthesia mediates cognitive dysfunction and is exacerbated in Aβ depositing brains. Taken together with results from prior studies, the data suggest that surprising and multiple mechanisms contribute to neural hyperexcitability. The data also suggest that IIS during sleep may be a biomarker for early detection of AD