Use this URL to cite or link to this record in EThOS:
Title: Understanding the role of dopamine in pathology and cognition in Huntington's disease
Author: Harris, Kate
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Thesis embargoed until 01 Jan 2400
Access from Institution:
Huntington’s disease is a genetic neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene. Dysfunction of dopamine (DA) signalling is thought to drive several of its clinical manifestations. DA receptors in frontostriatal pathways are lost early in the disease course – a possible compensatory response to increased dopaminergic activity, which is responsible for the hyperkinetic movement disorder of HD. DA signalling in frontostriatal pathways is also critical for cognitive processes such as executive function, and disruption of normal DA signalling may therefore contribute to cognitive impairments in HD. This thesis presents a number of clinical and laboratory studies, aiming to explore the importance of dopaminergic signalling in the pathogenesis of HD, and their contribution to the observed cognitive deficits. I first sought to explore the impact of DA modulation on cognitive function in HD. Firstly, using longitudinal data from the ENROLL-HD study, I have shown that the use of DA antagonists was associated with accelerated cognitive decline in early stage HD. I then performed an interventional study, in which cognitive function was characterised after administration of sulpiride (a D2 receptor-antagonist). Whilst sulpiride resulted in impaired executive function, there were improvements in other areas of dopamine-dependent cognition, such as reward-based decision-making and facial expression recognition. Taken together, these results suggest that DA signalling contributes to cognitive manifestations of HD. This relationship is complex, with D2 antagonism demonstrating opposing effects on different aspects of cognition. I next sought to characterise the anatomical and cellular basis for such deficits, as it appeared likely that these tasks involved other regions in addition to frontostriatal pathways. The hippocampus is known to play an important role in cognition, in particular in spatial memory, novelty encoding and reward processing. Given that DA has been shown to exert a modulatory influence on hippocampal neuronal and synaptic activity, I hypothesised that HD patients may also display hippocampal-related cognitive deficits. HD mice models have shown deficits in hippocampal synaptic plasticity, but little work has been done on hippocampal function in HD in humans. I therefore administered a hippocampal-dependent spatial memory task to HD gene carriers and found that early stage patients demonstrated impairments. The question as to whether the cause of such deficits had a possible DA basis led to the subsequent studies that I undertook. Evidence shows that glial cells play important roles in the pathogenesis of neurodegenerative diseases, and astrocytes have recently been shown to be involved in DA signalling. Specifically, DA activity at astrocyte DA receptors has neurotrophic and anti-inflammatory properties, and also increases intracellular Ca2+ transients in astrocytes, leading to the release of gliotransmitters which regulate synaptic plasticity. Astrocyte dysfunction in the hippocampus may therefore contribute to the DA-dependent deficits in HD. In order to explore this relationship, I studied the expression of DA receptors on hippocampal astrocytes in the R6/1 mouse model of HD. The number of D2 DA receptors was reduced in R6/1 mice in comparison to wild-type mice, suggesting a new mechanism by which DA signalling may contribute to HD pathogenesis and warranting further study. In summary, these findings together suggest that DA signalling plays an important, but complex role in the cognitive manifestations of HD, which extends to deficits in the hippocampus in addition to frontostriatal regions. Understanding this relationship further will have important implications for therapeutic targeting of the DA system in HD.
Supervisor: Barker, Roger Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Neuroscience ; Neurodegeneration ; Huntington's disease