Department or Program

Neuroscience

Abstract

Synaptic vesicles are individual, uniform packets of neurotransmitters that transmit signals when they fuse to the presynaptic membrane. However, the mechanisms that regulate the quantity of neurotransmitters packaged into synaptic vesicles are not understood. Partially filled vesicles cause impaired signaling (Prado et al. 2006; de Castro et al. 2009; Lima et al. 2010), and vesicles are not maximally filled (Song et al. 1997; Pothos et al. 2000; Wojcik et al. 2004). What controls this set-point? The same vesicular proteins responsible for neurotransmitter loading may also determine fusion competence. Prior work has ruled out neurotransmitter quantity as a prerequisite for vesicle fusion (Ernstrom personal communication; Parsons et al. 1999), but has instead suggested a role of the pH gradient generated by the V-ATPase proton pump (Ernstrom personal communication; Rost et al. 2015). If a vesicle pH threshold is a determinant for vesicle release, then we expected to recover genetic variants where V-ATPase activity is correlated with vesicle fusion. To test this model, we screened candidate V-ATPase mutants in genetically tractable nematodes, Caenorhabditis elegans, for their sensitivity to the nematicide organophosphate, aldicarb. Aldicarb causes toxic, paralyzing accumulation of neurotransmitters in the neuromuscular junction between neurons and muscles. Animals that are resistant to the paralyzing effects of aldicarb typically have a defect in neurotransmitter release, while hypersensitive animals typically have abnormally high rates of neurotransmitter release (Mahoney et al. 2006). This thesis will present the quantitative analysis of V-ATPase mutants where the molecular mutations have been mapped, but the aldicarb sensitivity phenotypes have not been characterized. We identified resistance and hypersensitivity in two mutant strains respectively, suggesting a possible role of V-ATPase proton pump acidification in vesicle fusion competency.

Level of Access

Open Access

First Advisor

Ernstrom, Glen

Date of Graduation

5-2024

Degree Name

Bachelor of Arts

Number of Pages

85

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