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Title: Mechanism of synaptic vesicle retrieval in epilepsy
Author: Clayton, Emma Louise
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2009
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Excessive release of neurotransmitter is a characteristic of epileptogenic cells. A number of lines of evidence implicate defects in the synaptic vesicle cycle as a cause of this excessive release. Synaptic vesicles are retrieved by more than one route in central nerve terminals. During mild stimulation the dominant synaptic vesicle retrieval pathway is classical clathrin mediated endocytosis. During elevated neuronal activity retrieval of synaptic vesicle membrane by bulk endocytosis is the predominant retrieval method. As it is triggered by strong stimulation, bulk endocytosis may be of importance in retrieval during epilepsy, however little is currently known about this pathway. In order to investigate the role of bulk endocytosis, we sought to establish a cell culture model of epilepsy, to develop an assay to distinguish retrieval by bulk endocytosis, and to use these tools to look at the molecular players controlling this form of endocytosis. Characterisation of bulk endocytosis through the development of tailored assay systems has revealed that bulk endocytosis is a fast event that is triggered during strong stimulation. Bulk endocytosis provides the nerve terminal with an appropriate mechanism to meet the demands of synaptic vesicle retrieval during periods of intense synaptic vesicle exocytosis. Inhibition of a dephosphorylation specific dynamin I-syndapin I interaction by competitive peptides inhibits activity dependent bulk endocytosis, implicating this interaction in a role in this method of synaptic vesicle retrieval. Having characterised the strength of stimulation needed to activate bulk endocytosis, and the speed at which it occurs, we also investigated the effects of known anti-epileptogenic drugs on bulk endocytosis in our central nerve terminal model system.
Supervisor: Cousin, Mike. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: epilepsy ; bulk endocytosis