Table_1_Characterization of Epileptic Spiking Associated With Brain Amyloidosis in APP/PS1 Mice.DOCX

Epileptic activity without visible convulsions is common in Alzheimer's disease (AD) and may contribute adversely to the disease progress and symptoms. Transgenic mice with amyloid plaque pathology also display epileptic seizures, but those are too infrequent to assess the effect of anti-epileptic treatments. Besides spontaneous seizures, these mice also display frequent epileptic spiking in epidural EEG recordings, and these have provided a means to test potential drug treatment to AD-related epilepsy. However, the origin of EEG spikes in transgenic AD model mice has remained elusive, which makes it difficult to relate electrophysiology with underlying pathology at the cellular and molecular level. Using multiple cortical and subcortical electrodes in freely moving APP/PS1 transgenic mice and their wild-type littermates, we identified several types of epileptic spikes among over 15 800 spikes visible with cortical screw electrodes based on their source localization. Cortical spikes associated with muscle twitches, cortico-hippocampal spikes, and spindle and fast-spindle associated spikes were present equally often in both APP/PS1 and wild-type mice, whereas pure cortical spikes were slightly more common in APP/PS1 mice. In contrast, spike-wave discharges, cortico-hippocampal spikes with after hyperpolarization and giant spikes were seen almost exclusively in APP/PS1 mice but only in a subset of them. Interestingly, different subtypes of spikes responded differently to anti-epileptic drugs ethosuximide and levetiracetam. From the translational point most relevant may be the giant spikes generated in the hippocampus that reached an amplitude up to ± 5 mV in the hippocampal channel. As in AD patients, they occurred exclusively during sleep. Further, we could demonstrate that a high number of giant spikes in APP/PS1 mice predicts seizures. These data show that by only adding a pair of hippocampal deep electrodes and EMG to routine cortical epidural screw electrodes and by taking into account underlying cortical oscillations, one can drastically refine the analysis of cortical spike data. This new approach provides a powerful tool to preclinical testing of potential new treatment options for AD related epilepsy.

在阿尔茨海默病（AD）中，无可见癫痫发作的活动十分普遍，并可能对疾病的进展和症状产生不利影响。携带淀粉样斑块病理的转基因小鼠也表现出癫痫发作，但这些发作过于罕见，无法评估抗癫痫治疗的效果。除了自发性癫痫发作外，这些小鼠在硬膜外脑电图（EEG）记录中也频繁出现癫痫样尖波，这为测试与阿尔茨海默病相关的癫痫的潜在药物治疗提供了一种手段。然而，转基因AD模型小鼠中EEG尖波的起源仍然难以捉摸，这使得在细胞和分子水平上将电生理学与其潜在病理联系起来变得困难。通过对自由移动的APP/PS1转基因小鼠及其野生型同胞小鼠的多皮质和皮质下电极进行使用，我们根据尖波源定位识别了多种类型的癫痫尖波，这些尖波在基于皮质螺钉电极可见的超过15,800个尖波中占有一席之地。与肌肉抽搐相关的皮质尖波、皮质-海马尖波以及与纺锤波和快速纺锤波相关的尖波在APP/PS1和野生型小鼠中出现的频率大致相同，而纯皮质尖波在APP/PS1小鼠中略微更为常见。相反，尖波-慢波放电、伴随去极化的皮质-海马尖波和巨大尖波几乎仅在APP/PS1小鼠中观察到，但仅限于其中的一部分小鼠。有趣的是，不同的尖波亚型对抗癫痫药物乙琥胺和左乙拉西坦的反应各不相同。从转化医学的角度来看，海马中产生的巨大尖波可能最为相关，这些尖波在颞叶通道中的振幅高达±5毫伏。与AD患者一样，它们仅在睡眠期间发生。此外，我们能够证明APP/PS1小鼠中大量巨大尖波的出现预示着癫痫发作。这些数据表明，通过仅在常规皮质硬膜外螺钉电极中添加一对海马深部电极和肌电图（EMG），并考虑潜在的皮质振荡，可以极大地提高皮质尖波数据分析的质量。这一新方法为阿尔茨海默病相关癫痫的潜在新治疗方案的预临床测试提供了一种强大的工具。