Defense Date

2013

Document Type

Thesis

Degree Name

Master of Science

Department

Anatomy & Neurobiology

First Advisor

Jeffrey Dupree

Abstract

Axonal pathology is a major contributor to impaired motor, sensory and cognitive dysfunction associated with multiple sclerosis particularly with the progressive forms of the disease. However, the early pathologic events responsible for axonal deterioration remain unclear. It is well recognized that maintaining proper axonal function is intimately related to proper establishment and maintenance of axonal domains such as the node of Ranvier and the axon initial segment (AIS). Numerous laboratories, including ours, have investigated the mechanisms that regulate node of Ranvier formation and maintenance. These studies have shown that node of Ranvier formation and maintenance require myelin contact. Interestingly, many of the same proteins that cluster at the node of Ranvier also cluster in the AIS; however, the mechanisms responsible for AIS clustering appear to be unique to the AIS as myelin contact is not required and the mechanisms appear to be intrinsic to the neuron. Determining how the AIS is developmentally generated is vital to a complete understanding of the AIS function. However, more in line with understanding the pathobiology of MS, our laboratory is interested in identifying the mechanisms responsible for the maintenance and restoration of AIS integrity and function. To achieve this goal, we have exploited the cuprizone toxicity model. This model results in a consistent course of demyelination followed by remyelination of layer V of the cerebral cortex. Using a combination of immunocytochemistry and confocal microscopy, we have analyzed AIS integrity as evidenced by the clustering of ankyrinG, a prominent initial segment protein. Our findings indicate that the number of AIS is not decreased following myelin loss. In addition, AIS length and surface area are not changed following demyelination. These findings are important as they suggest that myelin is not required for the maintenance of initial segment organization.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2013

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