Honors Theses
Date of Award
Spring 5-10-2025
Document Type
Undergraduate Thesis
Department
Biomolecular Sciences
First Advisor
Gregg Roman
Second Advisor
Brenton Laing
Third Advisor
Alberto Del Arco Gonzalez
Relational Format
Dissertation/Thesis
Abstract
Mammalian Unc13 (Munc13) and Drosophila Unc13 (Dunc13) are presynaptic active zone proteins essential for synaptic vesicle docking and priming in a neuron. Alcohol binds to the C1 domain of Munc13, which inhibits DAG binding. The reduction in DAG binding by Munc13 decreases the probability of vesicle fusion with the membrane, decreasing neurotransmitter release. Heterozygotes for a Dunc13 loss-of-function allele are behaviorally resistant to alcohol, physiologically resistant to alcohol, molecularly resistant to alcohol, and self-administer significantly more alcohol than control flies. Therefore, genetically reducing Dunc13 mimics a state of alcohol tolerance in the fly. The two main Dunc13 isoforms, Dunc13A and Dunc13B, have different roles in regulating alcohol sedation sensitivity. Genetically reducing Dunc13A leads to increased sensitivity to alcohol sedation, while genetically reducing Dunc13B leads to increased resistance to alcohol sedation. The two Dunc13 isoforms differentially interact with the presynaptic proteins RIM, Rab3, Rbp, and Liprin-α. Therefore, the goal of this work is to determine if these Dunc13 interacting proteins differentially regulate alcohol sedation sensitivity. The UAS-GAl4 system was used to reduce the genetic expression of the target proteins, and the FlyBar assay was used to compare alcohol sedation sensitivity and resistance between the fly genotypes. The genetic reduction of RIM, Rab3, and Rbp, which interact with Dunc13A, resulted in increased alcohol sedation sensitivity. Reduction of Liprin-α, which interacts with Dunc13B, also resulted in increased alcohol sensitivity despite the opposing effects of Dunc13A and Dunc13B on alcohol sedation sensitivity, suggesting that Liprin-α has Dunc13B-independent functions. The ability of RIM to increase alcohol sedation sensitivity when its expression is decreased and increase resistance when its expression is increased suggests that RIM plays a significant regulatory role in alcohol tolerance mechanisms.
Recommended Citation
Gundluru, Madhumitha, "The Role of Presynaptic Proteins In Alcohol Sensitivity And Tolerance" (2025). Honors Theses. 3278.
https://egrove.olemiss.edu/hon_thesis/3278
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