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synaptic formation, an effect regulated by MEF2-mediated post-translational modifications including acetylation (Mao et al., 1999; Shalizi et al., 2006). Furthermore, SIRT1 directly modulates many signal transduction pathways involved in synaptic plasticity and memory. In particular, SIRT1 modulates insulin/IGF-1 signaling through multiple mechanisms. It upregulates IGF-1 level by depressing IGFBP-1 [define!] (Lemieux et al., 2005) and augments insulin/IGF-1 signaling by deacetylating insulin receptor substrate-2 (IRS-2), which increases downstream signaling kinases, mitogen-activated protein kinase (MAPK) and PI3 kinase (Huang et al., 2008; Zhang, 2007a); Li et al., 2008 in press). Insulin/IGF-1 and its downstream signaling are important for synaptic plasticity and learning and memory. Mice with low IGF-1 levels exhibited impaired spatial learning, which was partially reversed by IGF-1 injection (Trejo et al., 2007). MAPK activation is also required for LTP (English and Sweatt, 1997) and for spatial learning and fear conditioning (Selcher et al., 1999).
All these studies suggest that SIRT1 may play an important role in synaptic plasticity and learning and memory. In the present study, we tested this hypothesis by evaluating synaptic plasticity and learning and memory in SIRT1 transgenic and knockout mice. Our results indicate that synaptic plasticity and several forms of learning and memory are impaired in SIRT1 knockout mice. On the other hand, spatial memory appears to be altered to a certain degree in SIRT1 over-expressing mice.
Object Description
| Title | Roles of SIRT1 in neuronal oxidative damage and brain function |
| Author | Li, Ying |
| Author email | lying@usc.edu; yingraceli@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-09-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Baudry, Michel Pike, Christian J. Madigan, Stephen A. |
| Abstract | Aging is a common phenomenon of multiple organisms. In humans aging is frequently accompanied by cognitive decline and occurrence of neurodegenerative diseases which reduce the quality of life and impose financial stress on society. Delaying the aging process, extending life span and decreasing the occurrence of age-related brain function deficit have always been aspirations of human kind. Extensive research has advanced our understanding of the mechanisms underlying aging, among which is the ability of calorie restriction to increase longevity, and the pivotal regulatory roles of insulin/IGF-1 signaling pathway. Some recent studies identified silent information regulator 2 (Sir2; SIRT1 is the mammalian homolog) as a key mediator of the beneficial effects of calorie restriction and this prompted development of SIRT1 activators for human consumption to delay aging and accompanying cognitive decline. However, our laboratory previously showed in yeast that Sir2 can increase stress sensitivity and limit life span extension under certain conditions, calling for more detailed characterization of SIRT1. In the research described in this dissertation I extended this study to the mammalian system and focused on the role of SIRT1 on the health of neurons and brain functions, especially learning and memory.; This dissertation consists of three chapters. In chapter 1 I briefly review some recent progress on aging, oxidative stress, insulin/IGF-1 signaling pathway and learning and memory with emphasis on the involvement of SIRT1 in these processes. In chapter 2 I focused on the role of SIRT1 in oxidative stress in neurons and its mechanisms. I found that SIRT1 inhibition increased resistance to oxidative damage and this effect is partially mediated by a reduction in IGF-I/IRS-2/Ras/ERK1/2 signaling. In chapter 3 I studied the functions of SIRT1 in learning and memory. The experiments showed that deletion of SIRT1 impairs a certain form of synaptic plasticity and reduce performance in several different learning and memory tasks while overexpressing SIRT1 did not substantially affect learning and memory.; Together, my studies reveal that SIRT1 exacerbates neuronal oxidative damage but is essential in learning and memory, indicating that SIRT1 plays multiple roles in aging and brain functions and that caution should be exercised in designing anti-aging or therapeutic approaches that involve targeting SIRT1. |
| Keyword | SIRT1; neurons; brain; oxidative damage; learning and memory |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1723 |
| Contributing entity | University of Southern California |
| Rights | Li, Ying |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LI-2405 |
| Archival file | uscthesesreloadpub_Volume44/etd-LI-2405.pdf |
Description
| Title | Page 75 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 65 synaptic formation, an effect regulated by MEF2-mediated post-translational modifications including acetylation (Mao et al., 1999; Shalizi et al., 2006). Furthermore, SIRT1 directly modulates many signal transduction pathways involved in synaptic plasticity and memory. In particular, SIRT1 modulates insulin/IGF-1 signaling through multiple mechanisms. It upregulates IGF-1 level by depressing IGFBP-1 [define!] (Lemieux et al., 2005) and augments insulin/IGF-1 signaling by deacetylating insulin receptor substrate-2 (IRS-2), which increases downstream signaling kinases, mitogen-activated protein kinase (MAPK) and PI3 kinase (Huang et al., 2008; Zhang, 2007a); Li et al., 2008 in press). Insulin/IGF-1 and its downstream signaling are important for synaptic plasticity and learning and memory. Mice with low IGF-1 levels exhibited impaired spatial learning, which was partially reversed by IGF-1 injection (Trejo et al., 2007). MAPK activation is also required for LTP (English and Sweatt, 1997) and for spatial learning and fear conditioning (Selcher et al., 1999). All these studies suggest that SIRT1 may play an important role in synaptic plasticity and learning and memory. In the present study, we tested this hypothesis by evaluating synaptic plasticity and learning and memory in SIRT1 transgenic and knockout mice. Our results indicate that synaptic plasticity and several forms of learning and memory are impaired in SIRT1 knockout mice. On the other hand, spatial memory appears to be altered to a certain degree in SIRT1 over-expressing mice. |
