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

Natalie Ness, Simon R. Schultz
doi: https://doi.org/10.1101/2020.10.08.330928
Natalie Ness
Centre for Neurotechnology and Department of Bioengineering, Imperial College London, South Kensington, London, SW7 2AZ, UK
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Simon R. Schultz
Centre for Neurotechnology and Department of Bioengineering, Imperial College London, South Kensington, London, SW7 2AZ, UK
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  • For correspondence: s.schultz@imperial.ac.uk
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Abstract

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.

Author Summary Cognitive decline in Alzheimer’s Disease (AD) correlates most strongly with dysfunction and loss of synapses in affected brain regions. While synaptic dysfunction is a well-established early symptom of AD, how impaired synaptic transmission may lead to progressive cognitive decline, remains subject to active research. In this study, we examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network. Place cells encode a cognitive map of an animal’s environment, enabling navigation and spatial memory. This provides a useful indicator of cognitive function, as place cell function is well characterized and abnormalities in place cell firing have been shown to underlie navigational deficits in rodents. We find that synapse loss in our network is sufficient to produce progressive impairments in place cell function, which resemble those observed in mouse models of the disease, supporting the hypothesis that synaptic dysfunction may underlie the cognitive impairment in AD. Furthermore, we observe that loss of excitatory and inhibitory synapses produce distinct spatial impairments. Future experiments investigating the relative contribution of different synaptic inputs may thus allow new insights into the neuronal network alterations in AD and potentially enable the identification of new therapeutic targets.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 09, 2020.
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A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease
Natalie Ness, Simon R. Schultz
bioRxiv 2020.10.08.330928; doi: https://doi.org/10.1101/2020.10.08.330928
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A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease
Natalie Ness, Simon R. Schultz
bioRxiv 2020.10.08.330928; doi: https://doi.org/10.1101/2020.10.08.330928

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