Stepwise breakdown of hippocampal neural circuits in Alzheimer's disease model mice

Abstract

Functional breakdown of neural microcircuits due to deposition of pathogenic proteins leads to cognitive dysfunctions in Alzheimer's disease (AD). AD patients show spatial and temporal cognitive dysfunctions as early symptoms, in which the hippocampus plays an essential role. However, the precise process leading to the breakdown of the hippocampal neural circuits of AD remains unclear. To address this issue, we performed chronic two-photon calcium imaging under a virtual reality environment to monitor spatiotemporal representations using AD model mice (AppNL-G-F) expressing a fluorescent calcium protein G-CaMP7. The activity of ~700 hippocampal CA1 pyramidal neurons was detected over months from the same neuronal populations. In AD mice, the rate of stable place cells started declining at 4 months before the number of place cells declined, and hyperactive cells increased from 7 months. Place cells were especially impaired near deposits of Aβ, suggesting toxicity of Aβ aggregates. In contrast, cells with temporal representation showed no impairment. These results are due to compensatory hyperactivity of the place cells near the Aβ aggregates, leading to the overall reduction of active place cells. Our chronic imaging using G-CaMP7-expressed AD mice could provide a novel view to evaluate the effects of a drug for AD progression.