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Title: Effects of activating KATP channel mutations on neuronal function
Author: McTaggart, James Suntac
ISNI:       0000 0004 2743 8539
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Gain of function mutations in the ATP sensitive potassium channel (KATP channel) cause a spectrum of disease in human beings. Some patients, with relatively severe mutations in the channel, present with diabetes mellitus in neonatal life along with neurological symptoms such as muscle hypotonia, balance problems, cognitive and motor developmental delay, and hyperactivity a syndrome known as iDEND. The most common iDEND causing mutation, the V59M mutation, has been modelled in a transgenic mouse, and the mutant channels may be expressed in specific cells of the body. In this thesis, I used mice with V59M KATP channels expressed in all neurons (the n V59M mouse), or in parvalbumin expressing neurons alone (the p V59M mouse). The electrical activity of cerebellar Purkinje cells was significantly inhibited in both of these mouse models. As cerebellar Purkinje cells provide the sole output from the cerebellar cortex, these results suggest that cerebellar dysfunction may be a feature of iDEND. Behavioural phenotyping of the p V59M mouse revealed that it was weaker and more hyperactive on free running wheels compared to controls. These phenotypes are reminiscent of the muscle hypotonia and hyperactivity of iDEND patients, which suggests that dysfunction of parvalbumin expressing neurons may contribute to the symptoms of iDEND. Consistent with the notion that cerebellar dysfunction is a feature of iDEND, patients performed worse than controls on a cerebellar dependent hand eye coordination task, and showed impaired coordination of eye movements. Taken together, the results presented in this thesis indicate that the neurological symptoms of iDEND may be dissected using the V59M mouse model. The possibilities for translation of these experimental results to clinical practice are discussed.
Supervisor: Ashcroft, Frances Mary Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Physiology and anatomy ; Medical Sciences ; Diabetes ; Neuroscience ; genetic disease ; iDEND ; KATP channel ; cerebellum