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.
Highlights
Alzheimer’s Disease (AD) is the most common cause of dementia, marked by progressive memory impairment and other cognitive deficits that lead to a loss of functional independence [1]
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
We examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network
Summary
AD is the most common cause of dementia, marked by progressive memory impairment and other cognitive deficits that lead to a loss of functional independence [1]. In patients and mouse models of AD, cognitive impairment correlates most strongly with synaptic dysfunction, which precedes cellular loss, suggesting AD is primarily a synaptopathology [4,5,6,7,8]. Recent neuroimaging studies have revealed that hyperactivity is the primary neuronal dysfunction in early AD, and may further exacerbate disease progression by increasing the release of amyloid β and tau protein [12,13,14]. An enhanced understanding of neuronal network alterations and the underlying actors may enable the identification of new therapeutic targets, and subtle changes in hippocampal activity provide promising early and -accessible biomarkers for diagnosis [17,18,19]
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