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Title: Age-dependent hippocampal network dysfuntion in a mouse model of alpha-synucleinopathy
Authors: Tweedy, Clare
Issue Date: 2019
Publisher: Newcastle University
Abstract: Aggregation of the protein alpha-synuclein (ASYN) is a key pathological feature of the alpha-synucleinopathies, a group of diseases including Lewy body dementia and Parkinson’s disease. A common symptom of alpha-synucleinopathy is cognitive dysfunction, and impairment in hippocampal gamma-frequency oscillations may underlie some of the cognitive deficits associated with ASYN pathology. The Thy-1 A30P mouse model overexpresses human mutant ASYN, with mice developing hippocampal spatial memory impairment by 12 months (Freichel et al. 2007). The aim of this thesis was to explore age-related hippocampal network changes in 2-4 month (A30P2+) mice and 10-13 month (A30P10+) mice to assess the effect of overexpression of mutant ASYN on hippocampal network activity in vitro. Using acute brain slice preparations of isolated hippocampi, A30P2+ mouse slices were found to exhibit excitatory/inhibitory network changes in region CA3 in the form of increased spontaneous sharp wave amplitude, increased frequency and amplitude of inhibitory postsynaptic potentials, and increased power of kainate-induced gamma-frequency oscillations. Immunohistochemistry revealed an increase in the density of parvalbuminpositive interneurons alongside a decrease in calbindin-positive interneurons. This change was accompanied by a more depolarised resting membrane potential in A30P2+ mouse CA3 pyramidal cells, and a sensitivity to interictal discharges in response to either kainate receptor agonism or GABAA receptor antagonism. With ageing, levels of excitability in A30P10+ mice were comparable to WT10+ mice. A30P10+ mice instead exhibited an impairment in cholinergic-induced, but not kainateinduced or spontaneous, gamma-frequency network oscillations. While mitochondrial dysfunction was not detectable with COX/SDH histochemistry until 15+ months in A30P mice, A30P10+ mice did show increased immunoreactivity for Iba1+ microglia. An environment of inflammation and excitotoxicity may be present in older A30P mice as a result of early network hyperexcitability, and this thesis explores early network changes in A30P mice and the wider dysfunction that follows
Description: PhD Thesis
Appears in Collections:Institute of Neuroscience

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