Department of Psychiatry, Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Nat Commun. 2022 Feb 16;13(1):886. doi: 10.1038/s41467-022-28551-x.
Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aβ) proteins, yet the neural circuit operations impacted during the initial stages of Aβ pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aβ throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aβ fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aβ-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.
早发性家族性阿尔茨海默病（AD）的特征是淀粉样β（Aβ）蛋白的大量积累，但在 Aβ发病机制的早期阶段受影响的神经回路操作仍不清楚。在这里，我们报告了 J20 转基因小鼠模型中内侧内嗅皮层（MEC）栅格细胞网络的编码损伤，该模型在整个海马体和内嗅皮层过度表达 Aβ。网格细胞表现出空间周期性、空间稳定性和与中间神经元和头方向细胞的同步性降低。相比之下，MEC 内的非网格细胞以及海马体中的位置细胞的空间编码仍然完整。网格细胞的缺陷出现在 Aβ纤维沉积的最早发病时，并与路径整合任务中空间记忆表现受损一致。这些结果表明，广泛的 Aβ介导的内嗅皮层-海马回路损伤导致内嗅皮层网格细胞网络的早期损伤。
