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Title: The role of calcium dependent neurotransmission in axon path finding, myelination and maintenance of specified cortical projection neuron populations
Author: Korrell, Kim
ISNI:       0000 0004 7966 0895
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The thesis examines the mechanisms involved in regulation of myelination during mammalian cortical development and the subsequent maintenance of the myelin in cortical projection neurons during adult life. Myelin in the central nervous system is produced by oligodendrocytes to ensure fast saltatory conduction of action potentials at the nodes of Ranvier, the gaps left by myelin. Myelination in the central nervous system is among others dependent on neuronal activity but the underlying mechanism is not yet completely understood. Because myelination plays an important role in many neuronal diseases, such as multiple sclerosis and schizophrenia, it is important to understand the molecular and cellular mechanisms. To do so, I examined the effects of genetically suppressing the neuronal activity in two separate ways in deep cortical layers of the mouse. One way to reduce neuronal activity was to abolish regulated vesicular release by removing Snap25 (synaptosome-associated protein of 25 kDA), member of the SNARE ((N-ethylmaleimide-sensitive factor) Attachment Protein Receptor) complex in a Snap25-flox mouse in which the essential exon 5a/b is flanked by LoxP sites and therefore truncated in the presence of Cre-recombinase. Since the fusion of neurotransmitter containing vesicles is mediated amongst others by the SNAP25 protein, removal of the functional SNAP25 protein prevented calciumdependent regulated vesicle exocytosis in a cell-type specific manner. Nrsr1 (for Layer VI) and Rbp4 (for Layer V) conditional Snap25 KO mice were bred on a floxed-stop-tdTomato background such that all affected cells were tdTomatolabelled within the subpopulation of layer V or VI projection neurons. My results for layer VI and Layer V demonstrated that preventing neurotransmitter release in Snap25 cKO mice does not affect the onset of myelination, density of oligodendroglia, nodal structure or thalamic fibre targeting but it has the effect of premature fibre degeneration causing myelin degeneration and decreasing the gratio in the dorsal corticospinal tract. The time course of degeneration occurs in a cell type specific manner, layer V being the most sensitive for silencing. The second way to influence neuronal activity was by introducing the inwardly rectifying potassium channel (Kir2.1) by in utero electroporation at the time of the cortical projection neuron generation. The overexpression of Kir2.1 lowers the probability of action potential formation through hyperpolarization of the neurons which leads to a decrease of the membrane resistance so that they are less excitable. Examining this model at various stages did not reveal differences in targeting of projections or myelin in the corpus callosum when assessed by MBP immunohistochemistry at P14. Together, the results indicate that neuronal activity has little effect on the onset of myelination but has effects on the g-ratio in deep cortical layer projection neurons in mice.
Supervisor: Molnár, Zoltán ; Hoerder-Suabedissen, Anna Sponsor: Anatomial Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available