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

• Published in: PLoS computational biology Vol. 17; no. 6; p. e1009115
• Main Authors: Ness, Natalie, Schultz, Simon R.
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 16.06.2021; Public Library of Science (PLoS)
• Subjects: Abnormalities; Alzheimer's disease; Animal models; Biology and Life Sciences; Cognitive ability; Competition; Computational grids; Computational neuroscience; Development and progression; Feedback; Firing rate; Health aspects; Impairment; Medicine and Health Sciences; Memory; Neurodegeneration; Neurodegenerative diseases; Presenilin 1; Pyramidal cells; Representations; Research and Analysis Methods; Simulation; Stability; Synapses; Transformation; Transformations (mathematics); United Kingdom
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1009115

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.