2023 Volume 158 Issue 2 Pages 144-149
Alzheimer’s disease (AD) patients cause cognitive impairment in time and space as early symptoms, in which the hippocampus plays an essential role. In the hippocampus, place cells play an important role in processing spatial information. The hippocampus recognizes space and guides creatures to their destinations using these place cells. In AD patients, the hippocampal neuronal network that place cells form could malfunction with age. However, it has remained unknown how the disruption of the neural circuits progresses at a single-cell resolution in AD. Conventional methods such as electrophysiology experiments could only record the same cells in the hippocampal neural circuit of awake mice for a few days. To clear the detail of neuronal circuit disruption in AD, it is necessary to observe brains of the same individuals over several months. Therefore, we performed chronic two-photon calcium imaging using AD model mice expressing the fluorescent calcium sensor protein G-CaMP7 to monitor spatiotemporal representation in a virtual reality environment. The activity of hundreds of hippocampal CA1 pyramidal neurons was detected over months from the same neuronal populations. In AD mice, amyloid (Aβ) plaque-like aggregates in the stratum oriens layer of hippocampal CA1 start to develop at 2.5 months of age, increase in both number and size with age, and neurons with hyperactivity increase near Aβ plaque-like aggregates. In addition, place cells observed during VR navigation showed abnormalities in the stability of activity within the place field at 4 months old, and then the stability was further deteriorated and the number of place cells decreased at 7 months old. Thus, we demonstrated that the activity patterns of various neurons, including place cells, in the neural circuitry of the hippocampal CA1 region in AD have different failure modes, and this finding is expected to be applied to the effective drug evaluation for AD.
