Krasnow, AM; (2017) Regulation of myelinated axon structure in the Central Nervous System. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Historically, research efforts into understanding the biology of the nervous system were focused primarily on the grey matter. However, more than half of the volume of human brain is composed of white matter, an area filled with myelinated axons, glial cells and blood vessels, which facilitates rapid transmission of information between distinct grey matter regions. The development of myelin is essential for normal brain function, white matter plasticity is increasingly invoked as a learning mechanism, and myelinated axon damage disrupts cognitive and motor function in a range of disorders. In this thesis I describe the results of experiments using transgenic animals, calcium and time-lapse imaging, pharmacology and electrophysiology to investigate two aspects of white matter physiology, the development of myelin and plasticity of white matter in the central nervous system. The structure of white matter is dynamic, changing in response to neuronal activity, but how action potentials regulate myelination by oligodendrocytes is uncertain. In the zebrafish spinal cord, I show that neuronal activity raises [Ca2+]i in developing oligodendrocytes in vivo. Myelin sheath elongation is associated with a high frequency of [Ca2+]i transients, and occurs ~1 hour after a [Ca2+]i elevation. Sheath shortening is associated with a low frequency of [Ca2+]i transients and the occurrence of long duration [Ca2+]i bursts. Thus, changes in [Ca2+]i control myelin sheath development. During ischaemia, glutamate release leads to an elongation of the node of Ranvier, which raises the question of whether physiological variations in glutamate levels might tune the conduction speed of myelinated axons via a similar mechanism. In rodent brain slices, I show that glutamate receptor agonists induce a reversible increase in node length. The mechanism of this glutamate-induced elongation is Ca2+-dependent and involves AMPA receptors and neuronal activity. These data show that neuronal activity regulates the length of myelin sheaths, and perhaps nodes, and will thus alter the speed of information propagation in the CNS.

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