Hippocampal place cells exhibit impairments in spatial information coding in an APP‐knock in model of Alzheimer’s Disease

Abstract Background The hippocampus is one of the first cortical regions to exhibit Alzheimer’s Disease (AD) pathology. The spatially‐related firing of hippocampal place cells provides the cellular basis for spatial memory and this is impaired relatively early in AD, yet few studies examine place cell activity in AD mouse models. We undertook an in‐depth characterisation of hippocampal pyramidal cell activity in an APP knock‐in model of AD. Method Microdrives carrying 8 tetrodes were implanted into the left CA1 hippocampal subfield of 14‐month female mice (four APP NL‐G‐F , four wild‐type littermates). Mice undertook daily foraging sessions in an open field and ran on a linear track as CA1 activity was recorded. On completion of experiments, 40µm coronal sections of fixed brain tissue were stained using Cresyl Violet to verify tetrode placement and Thioflavin‐S to quantify amyloid β plaque burden. Result 270 cells were recorded (119 wild‐type, 151 APP NL‐G‐F ). CA1 pyramidal cells were classified as “place cells” or “non‐place cells” based on their spatial information content (bits/spike). Pyramidal cells recorded in wild‐type mice had significantly greater spatial information content than APP NL‐G‐F pyramidal cells (Figure 1), and a higher proportion were classified as place cells. Wild‐type place cells had significantly greater spatial information content than APP NL‐G‐F place cells. Corresponding differences were identified in place field size (Figures 2, 3). A positive correlation was identified between Aβ plaque burden and pyramidal cell spatial information content in the four APP NL‐G‐F mice (Figure 4). Coordination of place cell firing by the hippocampal theta rhythm was disrupted in APP NL‐G‐F mice; phase‐locking of pyramidal cells and place cells was significantly reduced (Figure 5), there was less coherence in the preferred theta phase across the pyramidal cell population, and a reduction in theta phase precession was observed. Conclusion APP NL‐G‐F CA1 place cells exhibited deficits in both rate coding and temporal coding of spatial information indicating that amyloid β pathology, in the absence tau tangles, was associated with a disruption of hippocampal place cell function. These results provide preliminary support for the hypothesis that disruption of hippocampal function by AD pathology manifests as altered place cell activity and spatial behaviour.