Lisgaras Christos Panagiotis, Scharfman Helen E
bioRxiv. 2023 Aug 16:2023.04.24.537999. doi: 10.1101/2023.04.24.537999.
Interictal spikes (IIS) occur in 3 mouse lines with Alzheimer's disease featuresIIS in all 3 mouse lines were most frequent during rapid eye movement (REM) sleepThe dentate gyrus showed larger IIS and earlier current sources vs. CA1 or cortexChemogenetic silencing of medial septum (MS) cholinergic neurons reduced IIS during REMMS silencing did not change REM latency, duration, number of bouts or theta power.
Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's 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.
在3种具有阿尔茨海默病特征的小鼠品系中出现发作间期棘波（IIS）
所有3种小鼠品系中的IIS在快速眼动（REM）睡眠期间最为频繁
与CA1区或皮质相比，齿状回显示出更大的IIS和更早的电流源
内侧隔核（MS）胆碱能神经元的化学遗传学沉默减少了REM期间的IIS
MS沉默并未改变REM潜伏期、持续时间、发作次数或θ波功率。
发作间期棘波（IIS）是阿尔茨海默病（AD）及临床前模型中常见的一种异常电活动类型。IIS最大的脑区尚不清楚，但这很重要，因为此类数据将提示促成IIS产生的部位。由于海马体和皮质在AD模型中表现出兴奋性改变，我们探究了在皮质 - CA1 - 齿状回（DG）背腹轴上，IIS期间哪些区域主导活动。由于IIS通常出现时内侧隔核（MS）胆碱能神经元过度活跃，我们还测试了一个新假说，即选择性沉默MS胆碱能神经元会减少IIS。
我们使用模拟AD某些方面的小鼠：Tg2576小鼠、早老素2（PS2）基因敲除小鼠和Ts65Dn小鼠。为了选择性沉默MS胆碱能神经元，将Tg2576小鼠与胆碱乙酰转移酶（ChAT） - Cre小鼠杂交，其后代在MS中注射编码仅由设计药物（DREADDs）激活的抑制性设计受体的腺相关病毒（AAV）。我们在清醒、慢波睡眠（SWS）和快速眼动（REM）睡眠期间使用硅探针记录皮质 - CA1 - DG轴沿线的局部场电位。
我们在所有转基因或基因敲除小鼠中检测到IIS，但在年龄匹配的对照小鼠中未检测到。IIS在整个皮质 - CA1 - DG轴上均可检测到，且主要发生在REM睡眠期间。在所有3种小鼠品系中，DG颗粒细胞层中的IIS振幅明显大于CA1锥体细胞层或上方皮质中的振幅。电流源密度分析显示DG中有强大且早期的电流源，CA1区和皮质中也有其他电流源。MS胆碱能神经元的选择性化学遗传学沉默显著降低了REM睡眠期间的IIS发生率，而不影响REM的总持续时间、发作次数、REM睡眠潜伏期或REM期间的θ波功率。值得注意的是，两种对照干预均无效果。
DG中IIS始终具有最大振幅和强大电流源，这表明DG在IIS期间异常活跃。此外，在MS过度活跃时选择性降低MS胆碱能张力可能是减少AD中IIS的一种新策略。
