Disruption of the grid cell network in a mouse model of early Alzheimer's disease.

Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aß) proteins, yet the neural circuit operations impacted during the initial stages of Aß 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 Aß 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 Aß fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aß-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.

A non-spatial account of place and grid cells based on clustering models of concept learning.

One view is that conceptual knowledge is organized using the circuitry in the medial temporal lobe (MTL) that supports spatial processing and navigation. In contrast, we find that a domain-general learning algorithm explains key findings in both spatial and conceptual domains. When the clustering model is applied to spatial navigation tasks, so-called place and grid cell-like representations emerge because of the relatively uniform distribution of possible inputs in these tasks. The same mechanism applied to conceptual tasks, where the overall space can be higher-dimensional and sampling sparser, leading to representations more aligned with human conceptual knowledge. Although the types of memory supported by the MTL are superficially dissimilar, the information processing steps appear shared. Our account suggests that the MTL uses a general-purpose algorithm to learn and organize context-relevant information in a useful format, rather than relying on navigation-specific neural circuitry.

Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease.

The earliest stages of Alzheimer's disease (AD) are characterized by the formation of mature tangles in the entorhinal cortex and disorientation and confusion when navigating familiar places. The medial entorhinal cortex (MEC) contains specialized neurons called grid cells that form part of the spatial navigation system. Here we show in a transgenic mouse model expressing mutant human tau predominantly in the EC that the formation of mature tangles in old mice was associated with excitatory cell loss and deficits in grid cell function, including destabilized grid fields and reduced firing rates, as well as altered network activity. Overt tau pathology in the aged mice was accompanied by spatial memory deficits. Therefore, tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD.