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Dissertation
Irisin Regulation of Glutamatergic Synaptogenesis
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2025
DOI:
https://doi.org/10.7273/000007396
Abstract
The exerkine irisin was previously identified as a hormonal link mediating the positive effects of exercise in adult mammals on central Brain-Derived Neurotrophic Factor (BDNF) levels with the downstream consequence of increasing hippocampal synaptogenesis, which promotes learning and memory. A role for irisin in hippocampal synaptic development had not previously been elucidated, however these putative neurotrophic actions suggested an effect that phenocopies that of the previously-characterized neurotrophic adipokine, leptin. Characterizing neurotrophin regulation, signaling, and expression during development is critical for understanding the mechanisms underlying typical and atypical neurodevelopment, which is essential for clarifying the etiology of non-monogenic neurodevelopmental disorders.
In this dissertation, I investigated the mechanisms by which irisin mediates leptin-stimulated synaptogenesis in cultured neurons and by which irisin contributes to regulating mitochondrial function in cultured neurons. In my first study, I used complementary analyses of gene expression, fluorescence microscopy, and electrophysiology. I reported that irisin expression is necessary for leptin’s neurotrophic effects, while irisin alone is sufficient to stimulate synaptogenesis in in vitro models of developing hippocampal neurons. I further showed that leptin positively regulates irisin transcription, and that brain-derived neurotrophic factor is downstream of, and required for, the effects of both leptin and irisin on synaptogenesis. In my second study, I used complementary assays of gene expression, mitochondrial respiration and membrane potential, and fluorescence microscopy. I showed that irisin increases mitochondrial respiration, mitochondrial membrane potential, and synaptogenesis through a mechanism involving the brain-expressed uncoupling proteins, UCP2 and UCP4 but not UCP5. I further demonstrated that these uncoupling proteins exert differential effects on basal mitochondrial and synaptic phenotypes in hippocampal neurons. In conclusion, I have shown that irisin exerts neurotrophic effects in the developing hippocampus and have elucidated two mechanisms underlying this effect.
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Details
- Title
- Irisin Regulation of Glutamatergic Synaptogenesis
- Creators
- Mary Rose Josten
- Contributors
- Gary A. Wayman (Chair)Suzanne Appleyard (Committee Member)Michael Varnum (Committee Member)Heiko Jansen (Committee Member)Erica Crespi (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 171
- Identifiers
- 99901220475801842
- Language
- English
- Resource Type
- Dissertation