Identifying effective strategies to prevent memory loss in AD has eluded researchers to date, and likely reflects insufficient understanding of early pathogenic mechanisms directly affecting memory encoding. As synaptic loss best correlates with memory loss in AD, refocusing efforts to identify factors driving synaptic impairments may provide the critical insight needed to advance the field. In this study, we reveal a previously undescribed cascade of events underlying pre and postsynaptic hippocampal signaling deficits linked to cognitive decline in AD. These profound alterations in synaptic plasticity, intracellular Ca2+ signaling, and network propagation are observed in 3–4 month old 3xTg-AD mice, an age which does not yet show overt histopathology or major behavioral deficits. In this study, we examined hippocampal synaptic structure and function from the ultrastructural level to the network level using a range of techniques including electron microscopy (EM), patch clamp and field potential electrophysiology, synaptic immunolabeling, spine morphology analyses, 2-photon Ca2+ imaging, and voltage-sensitive dye-based imaging of hippocampal network function in 3–4 month old 3xTg-AD and age/background strain control mice. In 3xTg-AD mice, short-term plasticity at the CA1-CA3 Schaffer collateral synapse is profoundly impaired; this has broader implications for setting long-term plasticity thresholds. Alterations in spontaneous vesicle release and paired-pulse facilitation implicated presynaptic signaling abnormalities, and EM analysis revealed a reduction in the ready-releasable and reserve pools of presynaptic vesicles in CA3 terminals; this is an entirely new finding in the field. Concurrently, increased synaptically-evoked Ca2+ in CA1 spines triggered by LTP-inducing tetani is further enhanced during PTP and E-LTP epochs, and is accompanied by impaired synaptic structure and spine morphology. Notably, vesicle stores, synaptic structure and short-term plasticity are restored by normalizing intracellular Ca2+ signaling in the AD mice. These findings suggest the Ca2+ dyshomeostasis within synaptic compartments has an early and fundamental role in driving synaptic pathophysiology in early stages of AD, and may thus reflect a foundational disease feature driving later cognitive impairment. The overall significance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic vesicle stores, synaptic plasticity, and network propagation, which directly impact memory encoding.

中文翻译：

---

减少的突触前小泡存储介导阿尔茨海默氏病的早期小鼠模型中的细胞和网络可塑性缺陷

迄今为止，确定有效的策略来预防AD记忆丧失的研究人员还不了解，并且可能反映出对直接影响记忆编码的早期致病机制的了解不足。由于突触丧失与AD的记忆力丧失最佳相关，因此重新集中精力确定驱动突触损伤的因素可能会为推进该领域提供关键的见识。在这项研究中，我们揭示了突触前和突触后海马信号缺陷与AD认知功能下降相关的先前未描述的事件级联。在3-4个月大的3xTg-AD小鼠中观察到突触可塑性，细胞内Ca2 +信号传导和网络传播的这些深刻变化，该年龄尚未显示出明显的组织病理学或主要的行为缺陷。在这项研究中，我们使用了包括电子显微镜（EM），膜片钳和场电位电生理学，突触免疫标记，脊柱形态分析，2-光子Ca2 +成像和电压检测在内的一系列技术，从超微结构水平到网络水平研究了海马突触的结构和功能。 3-4个月大的3xTg-AD和年龄/背景应变控制小鼠的海马网络功能基于染料的敏感染料成像。在3xTg-AD小鼠中，CA1-CA3 Schaffer侧突触的短期可塑性受到了严重损害。这对于设定长期可塑性阈值具有更广泛的意义。自发性囊泡释放的变化和成对脉冲促成牵涉到突触前信号异常，并且EM分析显示，CA3末端中突触前囊泡的随时可释放和储备池减少。这是该领域的全新发现。同时，由LTP诱导的破伤风引发的CA1棘突触诱发的Ca2 +的增加在PTP和E-LTP时期期间进一步增强，并伴有突触结构和脊柱形态受损。值得注意的是，通过使AD小鼠中的细胞内Ca 2+信号传导正常化，可以恢复囊泡的储存，突触结构和短期可塑性。这些发现表明，在AD的早期阶段，突触区室中的Ca 2+异位稳态在驱动突触病理生理学中具有早期和基本的作用，因此可能反映出导致后期认知障碍的基础疾病特征。总体意义是确定影响突触小泡储存，突触可塑性，