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Modulation of presynaptic function: The role of protein ubiquitination and the effects of environmental toxins

  • Author(s): Myers, Katherine
  • Advisor(s): Schweizer, Felix E
  • et al.
Abstract

The nervous system rapidly integrates sensory modalities with higher order cognition to generate a seamless and appropriate output in the form of motor activity, behavior and cognitive functions. In order to do so, modification within neural circuits, individual cells and unique synapses is constantly occurring. In this dissertation, I focused on the problem of rapid modifications at pre-synaptic sites, and how those modifications generate information transfer in the form of synaptic vesicle release. In the first section of this dissertation, I examined the role of synaptic protein ubiquitination in modulating pre-synaptic release properties. In the second and third sections of the dissertation, I characterized the effects of agricultural pesticides, in particular ziram, on synaptic transmission. Electrophysiological recordings of mammalian neurons acutely exposed to inhibitors of ubiquitination indicate that disrupting the pathway at various points in the ubiquitin cycle leads to enhanced spontaneous release in a matter of minutes. Imaging with fluorescent reporters of exo and endocytosis further suggest a role for synaptic protein ubiquitination in modulating evoked release within the same time frame; inhibitors rapidly reduced the amount of stimulated exocytosis, possibly through or in parallel to disruption of endocytosis and synaptic vesicle recycling. Similar techniques were employed to examine the effects of ziram and other pesticides which are linked to an increased risk of Parkinson’s disease (PD) at mammalian and invertebrate synapses. Drosophila melanogaster larvae expressing either fluorescent sensors of exo and endocytosis, calcium, or voltage were used to measure changes in release at glutamatergic and aminergic neurons of the neuromuscular junction (NMJ) exposed to ziram. Combined, data from the NMJ and mammalian neurons demonstrated that ziram and other dithiocarbamate chemicals enhance spontaneous synaptic vesicle fusion and lead to spontaneous neural activity in aminergic neurons. Ziram leads to a depolarization of membranes, and differences in the outcome following exposure at different neurons may be related to pre-synaptic ion channel composition. These data offer insight into the dynamic modulation of release properties via ubiquitination, and offer insight into pre-synaptic changes in excitability that may occur in the onset and during the development of PD linked to environmental toxins.

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