The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.

海马体很容易在阿尔茨海默病 (AD) 中恶化。然而，它是一种异质结构，这可能有助于 AD 进展过程中沿其间隔时间轴的差异体积变化。在这里，我们研究了两种转基因 AD (ADTg) 小鼠模型沿背腹轴的淀粉样蛋白斑块沉积。我们还在这些小鼠中使用膜片钳生理学来探测腹侧海马中 AD 发病机制的功能后果，我们发现与相应的背侧区域相比，老年 ADTg 组的斑块负荷显着更高。尽管背腹侧淀粉样蛋白负荷存在差异，老年 ADTg 小鼠的腹侧 CA1 锥体神经元表现出类似于先前在背侧神经元中报告的生理变化，表明 HCN 通道病，但缺乏加剧的超阈值住宿。此外，HCN 通道功能可以通过内质网的药理学操作来挽救。这些观察表明 AD 相关的 HCN 通道病出现在背侧和腹侧 CA1 锥体神经元中，但前者遇到了额外的综合障碍，即内在兴奋性降低。