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

HIGHLIGHTSO_LIInterictal spikes (IIS) occur in 3 mouse lines with Alzheimers disease features C_LIO_LIIIS in all 3 mouse lines were most frequent during rapid eye movement (REM) sleep C_LIO_LIThe dentate gyrus showed larger IIS and earlier current sources vs. CA1 or cortex C_LIO_LIChemogenetic silencing of medial septum (MS) cholinergic neurons reduced IIS during REM C_LIO_LIMS silencing did not change REM latency, duration, number of bouts or theta power C_LI Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimers disease (AD) and preclinical models. 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 which areas dominate the activity during IIS 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 MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials 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 or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.