Grid cell disruption in a mouse model of early Alzheimer’s disease reflects reduced integration of self-motion cues and increased influence of environmental geometry

Abstract

Grid cell impairments and path integration deficits are sensitive markers of early Alzheimer's disease (AD). Converging evidence from human and rodent studies suggest that disrupted grid coding underlies path integration deficits in preclinical individuals. However, it still remains unclear if disrupted early AD grid coding reflects increased noise across the network or a specific deficit in path integration, perhaps via an impairment in the integration of self-motion cues. Here, we report in the J20 transgenic amyloid beta mouse model of early AD that grid cells were spatially unstable towards the center of the square arena but not near the borders, had qualitatively different spatial components that aligned parallel to the borders of the environment, and exhibited impaired integration of distance travelled via reduced theta phase precession. Our results suggest that disrupted early AD grid coding reflects reduced integration of self-motion cues but not environmental landmarks, providing further evidence that grid cell impairments underlie specific path integration deficits in early AD.

Entorhinal‐based path integration selectively predicts midlife risk of Alzheimer's disease

“…This imitates PI deficits in APOE ε4 carriers and may reflect difficulty in grid anchoring or an inability to use a “purer” PI strategy 7,8 . This is consistent with previous work demonstrating the importance of natural locomotion for more accurate judgments of direction in humans and more robust spatial cell activity in rodents 54–56 . Additionally, our observation that defective angular estimation drove PI errors is also in line with increasing evidence that spatial navigation is underpinned by neuronal vector‐based coding 57,58 .…”

Spatial periodicity in grid cell firing is explained by a neural sequence code of 2-D trajectories

“…Notably, sequence coding of trajectories is not limited to physical space but could be useful for cognitive functions such as working memory or episodic memory that connects events into a cohesive story, consistent with experimental data demonstrating a grid-like code of conceptual knowledge space in humans 10 . A sequence code of trajectories by grid cells can thus explain data from human subjects that link reduced grid-like activity with path integration deficits observed in Alzheimer's disease risk carriers 64,65 , and data from rodent experiments demonstrating that grid cell firing is reduced in a rodent animal model of Alzheimer's disease 66,67 .…”