Learning, memory, and synaptic plasticity in Alzheimer’s model mice
Clark, Jason Knight
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Alzheimer’s disease (AD) is a neurodegenerative disease of aging thought to be initiated by production of Amyloid-β peptide, which leads to synaptic dysfunction and progressive memory loss, and the eventual formation of β-Amyloid plaques and neurofibrillary Tau tangles. Working memory is one of the first cognitive impairments in AD. We therefore wanted to explore the cellular mechanisms underlying working memory impairments in AD utilizing a well-known triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) carrying mutations in APP, PS1, and Tau. We evaluated working memory using an 8-arm radial maze, and synaptic transmission and plasticity using an ex vivo hippocampal slice preparation to measure field Excitatory Post-Synaptic Potentials (fEPSP) in the CA1 region of ventral hippocampus. Unexpectedly, young 3xTg-AD mice at 3 months of age, typically considered to be presymptomatic, were significantly impaired in the spatial working memory task compared to Nontransgenic (NonTg) control mice. Measurements of fEPSPs to evaluate Long-Term Potentiation (LTP) as an indicator of long-term synaptic plasticity showed the NMDA receptor-dependent component of LTP (NMDAR LTP) was reduced in 3xTg-AD mice compared to NonTg mice. The remaining non-NMDA receptor-dependent component of LTP (non-NMDAR LTP) however was increased, resulting in a total LTP that was not different between 3xTg-AD and NonTg mice. At 8 months of age, 3xTg-AD mice were again significantly impaired in the spatial working memory task, and NMDAR LTP was again reduced in 3xTg-AD mice. The non-NMDAR LTP however was also reduced in 3xTg-AD mice, resulting in a total LTP that was now reduced in 3xTg-AD mice. The majority (>90%) of non-NMDAR LTP is mediated by Voltage-Dependent Calcium Channels (VDCC), and attempts to block LTP using NMDAR and VDCC antagonists were unsuccessful, indicating 3xTg-AD mice have compensatory mechanisms for LTP expression that occur independently of NMDAR or non-NMDAR dependent mechanisms. In addition, 3xTg-AD mice also showed impairments in short-term synaptic plasticity and basal synaptic transmission at both 3 and 8 months of age. These impairments in synaptic transmission and plasticity coincide with impairments in spatial working memory, and understanding the nature of these altered mechanisms may lead to therapeutic targets for disorders such as AD.