Interictal spikes in Alzheimer's disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum

• DOI: 10.1016/j.nbd.2023.106294
• Publication Date: 2023-09-14T03:07:13Z
• Authors: Christos Panagiot...; Helen E. Scharfman
• Keywords: Mice, Knockout; Presenilin 2; Down syndrome; Cholinergic Agents; Neurosciences. Biological psychiatry. Neuropsychiatry; Alzheimer's disease; Interictal spikes; Article; Cholinergic Neurons; Mice; Alzheimer Disease; Cholinergic neurons; Dentate Gyrus; Animals; Amyloid precursor protein (APP); RC321-571

Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS largest not known but important because such data would suggest sites that contribute to generation. Because hippocampus cortex exhibit altered excitability AD models, we asked which areas dominate the during along cortical-CA1-dentate gyrus (DG) dorso-ventral axis. medial septal (MS) cholinergic neurons overactive when typically occur, also tested novel hypothesis silencing MS selectively reduce IIS. We used mice simulate aspects AD: Tg2576 mice, presenilin 2 (PS2) knockout Ts65Dn mice. To silence neurons, were bred with choline-acetyltransferase (ChAT)-Cre offspring injected AAV encoding inhibitory designer receptors exclusively activated by drugs (DREADDs). recorded local field potentials cortical-CA1-DG axis using silicon probes wakefulness, slow-wave sleep (SWS) rapid eye movement (REM) sleep. detected all transgenic or age-matched controls. detectable throughout occurred primarily REM In 3 mouse lines, amplitudes significantly greater DG granule cell layer vs. CA1 pyramidal overlying cortex. Current source density analysis showed robust early current sources DG, additional also. Selective chemogenetic reduced rate without affecting overall duration, number bouts, latency sleep, theta power REM. Notably, two control interventions no effects. Consistent maximal amplitude strong is remarkably active addition, reducing tone, at times hyperactive, could be new strategy AD.