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Investigating Cellular Biology of Cognitive Impairment in Down Syndrome using Mouse Models

Muza, Phillip Munashe; (2023) Investigating Cellular Biology of Cognitive Impairment in Down Syndrome using Mouse Models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Down syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability with an incidence of 1 in 800 live births worldwide. Using a mouse model of DS - Dp(10)2Yey – with only 37 out of a possible ~240 protein coding genes implicated in DS expressed in three copies, we investigated how these genes modulate cognitive function and cellular biology in brain regions associated with spatial cognition. Using a battery of behavioural assays, we observed spatial working memory and exploratory deficits in 3-month old female Dp(10)2Yey. Next, we wanted to investigate the cellular biology of Dp(10)2Yey mice. We developed a novel brain slice optical clearing and immunolabelling method, termed Affordable Brain Slice Optical Clearing (ABSOC), allowing us to quantify cell densities of calretinin (CR), neuropeptide-Y (NPY), and parvalbumin (PV) interneuron subtypes in the medial prefrontal cortex (mPFC) and dorsal hippocampus of male and female Dp(10)2Yey mice. We found robust changes in the distributions of NPY- and PV-positive cells in the mPFC of male and female Dp(10)2Yey mice, respectively, and moderate changes to CR-positive cells in the dorsal hippocampus of Dp(10)2Yey mice. Proportions of glial and neuronal cells are altered in DS, and so we investigated these populations in the hippocampus of male and female Dp(10)2Yey mice. We reported changes in S100B-positive cell density in male Dp(10)2Yey mice but not female Dp(10)2Yey mice. Finally, to understand the genetic mechanisms underlying cognitive impairment in Dp(10)2Yey mice, we are generating a mapping panel of Dp(10)2Yey mice made of three novel mouse models carrying three copies of ~13 genes from the 37 genes triplicated in Dp(10)2Yey mice. Overall, the results of this investigation show Dp(10)2Yey mice have behavioural impairments and robust changes in interneuron distribution within their brains – the small size of the genetic duplication in these mice makes them a tractable model to investigate genes causal for cognitive impairment in DS..

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating Cellular Biology of Cognitive Impairment in Down Syndrome using Mouse Models
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10166732
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