The effect of the brain derived neurotrophic factor pro-domain variants, val66 and met66, on neuronal activity
department or school: Science, Irving K. Barber Faculty of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Zurfluh, Noah
issued: 2024-08-06T22:03:32Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Synaptic plasticity is a key cognitive function that allows the brain to remain dynamic. It functions by strengthening and weakening synaptic connections in an activity-dependent manner. Cellular mechanisms such as long-term potentiation (LTP) and long-term depression of synapses (LTD) can induce functional and morphological changes and thereby alter synaptic strength. These changes to synaptic activity and structural integrity are regulated by neurotrophic factors. Any disruption in neurotrophic function, whether due to mutations or variations in expression levels, is likely to lead to imbalances in LTD/LTP dynamics. These imbalances, in turn, contribute to structural and functional alterations often associated with mental illnesses and cognitive dysfunctions. Notably, a mutation in the pro-domain of the brain-derived neurotrophic factor, termed Met66, has been associated with decreasing hippocampal volume and increasing the risk for anxiety, depression, and cognitive dysfunction. Interestingly, Dr. Gibon demonstrated that Met66 can disrupt neurotransmission, however, the mechanism behind how Met66 can interfere with neural activity is unknown. Two proposed mechanisms for Met66 have been proposed; either based on reducing BDNF levels or ligand binding effects. Considering that Met66 can reduce hippocampal volume as well as disrupt neuronal activity and that LTD is the mechanism responsible for synapse weakening and elimination, it was hypothesized that Met66 induces LTD in synapses. This hypothesis was tested by looking at various aspects of the LTD, including morphology, protein expression, and phosphorylation. The results showed that Met66 alone did not significantly alter Ca²âº dynamics, morphological changes, or BDNF signaling pathways. However, both Val66 and Met66 affected the pre-synaptic compartment by decreasing the level of SYN-1, while Met66 also affected the post-synaptic compartment by decreasing the PSD-95 protein expression. These observations sugge…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/88883
note: The Effect of the Brain Derived Neurotrophic Factor Pro-domain Variants, Val66 and Met66, on Neuronal Activity by Noah Zurfluh B.Sc., University of British Columbia, 2021 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE COLLEGE OF GRADUATE STUDIES (Biochemistry & Molecular Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) July 2024 © Noah Zurfluh, 2024 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis entitled: The Effect of the Brain Derived Neurotrophic Factor Pro-domain Variants, Val66 and Met66, on Neuronal Activity submitted by Noah Zurfluh in partial fulfillment of the requirements of the degree of Master of Science. . Dr. Philip A. Barker, Faculty of Science-Biology Supervisor Dr. Julien Gibon, Faculty of Science-Biology Co-Supervisor Dr. Isaac Lee, Faculty of Science-Chemistry Supervisory Committee Member Dr. Deanna Gibson, Faculty of Science-Biology Supervisory Committee Member Dr. Jonathan Little, Faculty of Health and Social Development University Examiner iii Preface This thesis represents the culmination of extensive laboratory work and analysis, all of which were conducted by me, Noah Zurfluh. I am proud to state that I was the sole contributor to the execution of all laboratory experiments and the primary author of this thesis. The identification and design of the research were collaboratively developed by Julien Gibon and myself. I performed all experiments and analyzed the resulting data unless explicitly stated otherwise in the thesis. Brett Bernard, an undergraduate student, assisted with the imaging of growth cones in one set of experiments and contributed to the analysis of that specific data. Svetlana Simtchouk was the creator of the PC12 P75NTR KO CRISPR cell line used in this thesis. Dr. Phil Barker and Julien Gibon provided invaluable guidance throughout the experimental processes, leveraging their e…
has type: Thesis/Dissertation
date issued: 2024-09
is shown at: 10.14288/1.0444992
language: eng
degree discipline: Biochemistry and Molecular Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Barker, Philip A.
contributor: Gibon, Julien
type: Text
identifier URI: http://hdl.handle.net/2429/88883