Interictal Spikes in Alzheimer’s Disease: Preclinical Evidence for Dominance of the Dentate Gyrus and Cholinergic Control by Medial Septum

Abstract

Interictal spikes (IIS) are a common type of abnormal electrical activity in animal models of Alzheimer′s disease (AD) and AD patients. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked where IIS are largest along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the medial septohippocampal cholinergic neurons selectively would reduce IIS. We used 3 models of AD, Tg2576 mice, presenilin 2 knockout mice, and the Ts65Dn mouse model of Down′s syndrome. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with ChAT-Cre mice and offspring mice were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs. We recorded EEG along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and were primarily during REM sleep. In all 3 models, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS frequency during REM sleep without affecting the overall duration or number of REM sleep bouts. Maximal IIS amplitude in the DG of 3 AD mouse models suggests that the DG could be one of the areas that contribute to IIS generation. Selectively reducing MS cholinergic tone could be a new strategy to reduce IIS in AD.