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An in vivo electrophysiological and computational analysis of hippocampal synaptic changes in the Alzheimer’s disease mouse

Squirrell, Daniel

[Thesis]. Manchester, UK: The University of Manchester; 2015.

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in the decline of cognitive function, memory formation and retrieval, and abrupt changes in person- ality. Damage to brain networks occur during prodromal stages of AD, prior to the development of clinical symptoms of dementia. Further characterising this state and identifying reliable biomarkers for early detection are priorities in AD research.I characterised neuronal changes within the dorsal CA1 and subiculum regions of the hippocampal formation (HF) in the well-characterised 3xTgAD mouse model of AD. These regions are well-established sites for early neurodegeneration in both AD patients and AD animal models. We inserted multi-electrode recording arrays into CA1 and subiculum of urethane anaesthetised 3xTgAD mice and recorded spontaneous local field potential activity. Using traditional and novel information theoretic approaches, I determined the information carrying capacity of the CA1- subiculum network during different network rhythms, and how this altered with age and AD-like pathology. A bipolar stimulating electrode was inserted into CA1, allowing the assessment of synaptic integrity between CA1 and subiculum.Results showed that synaptic and network changes occur in CA1 and subiculum during the early stages of AD-like pathology and correlates with the development of intracellular beta-amyloid. There is a progressive breakdown in synaptic facilitation as early as 3 months in the 3xTgAD mouse. These data support an advanced ageing-like phenotype in AD model mice, with an enhanced age/pathology-dependent breakdown in neuronal communication compared to age-matched controls. In agreement with other studies, 3xTgAD mice demonstrate evidence of pathology-related changes in the network rhythms of the HF. 3xTgAD mice show an increase in the power of alpha and beta rhythms, and a concurrent reduction in the power of delta oscillations. Application of novel information theoretic techniques results in a breakdown in the information carrying capacity of the hippocampal system. This deficit manifests as a reduction in information flow during delta-dominant periods of EEG rhythms, with a specific reduction during slow-wave ripple activity. This change in neuronal communication correlates with the onset of memory-retention/consolidation deficits. These network changes are complex, with alterations in the information carrying capacity of the system during theta rhythms at 6 months, and during slow-wave components by 9 months in the 3xTgAD mouse.This study provides the first evidence of an early and progressive decline in neuronal connectivity and communication that correlates with changes in cognition in the 3xTgAD mouse. Application of novel analytical techniques to multi-site EEG recording revealed early and measureable changes in information processing during the onset of AD-like pathology. These are important new biomarkers for early AD characterisation.